Carbamic acid compounds comprising an ester or ketone linkage as HDAC inhibitors

ABSTRACT

This invention pertains to certain carbamic acid compounds of the formula (I), which inhibit HDAC (histone deacetylase) activity: wherein: J is a linking functional group and is independently:—O —C(═O)— or —C(═O)—O — or —C(═O)—; Cy is a cyclyl group and is independently: C 3-20 carbocyclyl, C 3-20 heterocyclyl, or C 5-20 aryl; and is optionally substituted; Q 1  is a cyclyl leader group, and is independently a divalent bidentate group obtained by removing two hydrogen atoms from a ring carbon atom of a saturated monocyclic hydrocarbon having from  4  to  7  ring atoms, or by removing two hydrogen atoms from a ring carbon atom of saturated monocyclic heterocyclic compound having from  4  to  7  ring atoms including  1  nitrogen ring atom or  1  oxygen ring atom; and is optionally substituted; Q 2  is an acid leader group, and is independently: C 1-8 alkylene; and is optionally substituted; or: Q 2  is an acid leader group, and is independently: C 5-20 arylene; C 5-20 arylene-C 1-7 alkylene; C 1-7 alkylene-C 5-20 arylene; or C 1-7 alkylene-C 5-20 aryleneC 1-7 alkylene; and is optionally substituted; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC,and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.

RELATED APPLICATION

This application is the US national phase of International ApplicationPCT/GB2004/000147, filed 19 Jan. 2004, which designated the U.S. andclaims benefit of U.S. 60/440,616, dated 17 Jan. 2003, the entirecontents of each of which are hereby incorporated by reference.

TECHNICAL FIELD

This invention pertains generally to the field of biologically activecompounds, and more specifically to certain carbamic acid compoundswhich inhibit HDAC (histone deacetylase) activity. The present inventionalso pertains to pharmaceutical compositions comprising such compounds,and the use of such compounds and compositions, both in vitro and invivo, to inhibit HDAC, and in the treatment of conditions mediated byHDAC, cancer, proliferative conditions, psoriasis, etc.

BACKGROUND

Throughout this specification, including any claims which follow, unlessthe context requires otherwise, the word “comprise,” and variations suchas “comprises” and “comprising,” will be understood to imply theinclusion of a stated integer or step or group of integers or steps, butnot the exclusion of any other integer or step or group of integers orsteps.

It must be noted that, as used in the specification and any appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

Ranges are often expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by the use of the antecedent “about,” itwill be understood that the particular value forms another embodiment.

DNA in eukaryotic cells is tightly complexed with proteins (histones) toform chromatin. Histones are small, positively charged proteins whichare rich in basic amino acids (positively charged at physiological pH),which contact the phosphate groups (negatively charged at physiologicalpH) of DNA. There are five main classes of histones, H1, H2A, H2B, H3,and H4. The amino acid sequences of histones H2A, H2B, H3, and H4 showremarkable conservation between species, whereas H1 varies somewhat, andin some cases is replaced by another histone, e.g., H5. Four pairs ofeach of H2A, H2B, H3, and H4 together form a disk-shaped octomericprotein core, around which DNA (about 140 base pairs) is wound to form anucleosome. Individual nucleosomes are connected by short stretches oflinker DNA associated with another histone molecule (e.g., H1, or incertain cases, H5) to form a structure resembling a beaded string, whichis itself arranged in a helical stack, known as a solenoid.

The majority of histones are synthesised during the S phase of the cellcycle, and newly synthesised histones quickly enter the nucleus tobecome associated with DNA. Within minutes of its synthesis, new DNAbecomes associated with histones in nucleosomal structures.

A small fraction of histones, more specifically, the amino side chainsthereof, are enzymatically modified by post-translational addition ofmethyl, acetyl, or phosphate groups, neutralising the positive charge ofthe side chain, or converting it to a negative charge. For example,lysine and arginine groups may be methylated, lysine groups may beacetylated, and serine groups may be phosphorylated. For lysine, the—(CH₂)₄—NH₂ sidechain may be acetylated, for example by anacetyltransferase enzyme, to give the amide —(CH₂)₄—NHC(═O)CH₃.Methylation, acetylation, and phosphorylation of amino termini ofhistones which extend from the nucleosomal core affects chromatinstructure and gene expression. (See, for example, Spencer and Davie,1999).

Acetylation and deacetylation of histones is associated withtranscriptional events leading to cell proliferation and/ordifferentiation. Regulation of the function of transcription factors isalso mediated through acetylation. Recent reviews of histonedeacetylation include Kouzarides, 1999 and Pazin et al., 1997.

The correlation between the acetylation status of histones and thetranscription of genes has been known for over 30 years (see, forexample, Howe et al., 1999). Certain enzymes, specifically acetylases(e.g., histone acetyltransferase, HAT) and deacetylases (e.g., histonedeacetylase, HDAC), which regulate the acetylation state of histoneshave been identified in many organisms and have been implicated in theregulation of numerous genes, confirming the link between acetylationand transcription. See, for example, Davie, 1998. In general, histoneacetylation correlates with transcriptional activation, whereas histonedeacetylation is associated with gene repression.

A growing number of histone deacetylases (HDACs) have been identified(see, for example, Ng and Bird, 2000). The first deacetylase, HDAC1, wasidentified in 1996 (see, for example, Tauton et al., 1996).Subsequently, two other nuclear mammalian deacetylases were found, HDAC2and HDAC3 (see, for example, Yang et al., 1996, 1997, and Emiliani etal., 1998). See also, Grozinger et al., 1999; Kao et al., 2000; and Vanden Wyngaert et al., 2000.

Eleven (11) human HDACs have been cloned so far:

-   -   HDAC1 (Genbank Accession No. NP_(—)004955)    -   HDAC2 (Genbank Accession No. NP_(—)001518)    -   HDAC3 (Genbank Accession No. 015379)    -   HDAC4 (Genbank Accession No. MD29046)    -   HDAC5 (Genbank Accession No. NP_(—)005465)    -   HDAC6 (Genbank Accession No. NP_(—)006035)    -   HDAC7 (Genbank Accession No. MF63491)    -   HDAC8 (Genbank Accession No. AAF73428)    -   HDAC9 (Genbank Accession No. MK66821)    -   HDAC10 (Genbank Accession No. AAK 84023)    -   HDAC11 (Genbank Accession No. NM_(—)024827)

These eleven human HDACs fall in two distinct classes: HDACs 1, 2, 3 and8 are in class I, and HDACs 4, 5, 6, 7, 9, 10 and 11 are in class II.

There are a number of histone deacetylases in yeast, including thefollowing:

-   -   RPD3 (Genbank Accession No. NP 014069)    -   HDA1 (Genbank Accession No. P53973)    -   HOS1 (Genbank Accession No. Q12214)    -   HOS2 (Genbank Accession No. P53096)    -   HOS3 (Genbank Accession No. Q02959)

There are also numerous plant deacetylases, for example, HD2, in Zeamays (Genbank Accession No. AF254073_(—)1).

HDACs function as part of large multiprotein complexes, which aretethered to the promoter and repress transcription. Well characterisedtranscriptional repressors such as Mad (Laherty et al., 1997), pRb(Brehm et al., 1998), nuclear receptors (Wong et al., 1998) and YY1(Yang et al., 1997) associate with HDAC complexes to exert theirrepressor function.

The study of inhibitors of histone deacetylases indicates that theseenzymes play an important role in cell proliferation anddifferentiation. The inhibitor Trichostatin A (TSA) (Yoshida et al.,1990a) causes cell cycle arrest at both G1 and G2 phases (Yoshida andBeppu, 1988), reverts the transformed phenotype of different cell lines,and induces differentiation of Friend leukaemia cells and others(Yoshida et al., 1990b). TSA (and SAHA) have been reported to inhibitcell growth, induce terminal differentiation, and prevent the formationof tumours in mice (Finnin et al., 1999).

Trichostatin A (TSA)

Suberoylanilide Hydroxamic Acid (SAHA)

Cell cycle arrest by TSA correlates with an increased expression ofgelsolin (Hoshikawa et al., 1994), an actin regulatory protein that isdown regulated in malignant breast cancer (Mielnicki et al., 1999).Similar effects on cell cycle and differentiation have been observedwith a number of deacetylase inhibitors (Kim et al., 1999).

Trichostatin A has also been reported to be useful in the treatment offibrosis, e.g., liver fibrosis and liver cirrhosis. See, e.g., Geerts etal., 1998.

Recently, certain compounds that induce differentiation have beenreported to inhibit histone deacetylases. Several experimentalantitumour compounds, such as trichostatin A (TSA), trapoxin,suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have beenreported to act, at least in part, by inhibiting histone deacetylase(see, e.g., Yoshida et al., 1990; Richon et al., 1998; Kijima et al.,1993). Additionally, diallyl sulfide and related molecules (see, e.g.,Lea et al., 1999), oxamflatin (see, e.g., Kim et al., 1999; Sonoda etal., 1996), MS-27-275, a synthetic benzamide derivative (see, e.g.,Saito et al., 1999; Suzuki et al., 1999; note that MS-27-275 was laterre-named as MS-275), butyrate derivatives (see, e.g., Lea and Tulsyan,1995), FR901228 (see, e.g., Nokajima et al., 1998), depudecin (see,e.g., Kwon et al., 1998), and m-carboxycinnamic acid bishydroxamide(see, e.g., Richon et al., 1998) have been reported to inhibit histonedeacetylases. In vitro, some of these compounds are reported to inhibitthe growth of fibroblast cells by causing cell cycle arrest in the G1and G2 phases, and can lead to the terminal differentiation and loss oftransforming potential of a variety of transformed cell lines (see,e.g., Richon et al, 1996; Kim et al., 1999; Yoshida et al., 1995;Yoshida & Beppu, 1988). In vivo, phenybutyrate is reported to beeffective in the treatment of acute promyelocytic leukemia inconjunction with retinoic acid (see, e.g., Warrell et al.; 1998). SAHAis reported to be effective in preventing the formation of mammarytumours in rats, and lung tumours in mice (see, e.g., Desai et al.,1999).

The clear involvement of HDACs in the control of cell proliferation anddifferentiation suggests that aberrant HDAC activity may play a role incancer. The most direct demonstration that deacetylases contribute tocancer development comes from the analysis of different acutepromyelocytic leukemias (APL). In most APL patients, a translocation ofchromosomes 15 and 17 (t(15; 17)) results in the expression of a fusionprotein containing the N-terminal portion of PML gene product linked tomost of RARα (retinoic acid receptor). In some cases, a differenttranslocation (t(11; 17)) causes the fusion between the zinc fingerprotein PLZF and RARα. In the absence of ligand, the wild type RARαrepresses target genes by tethering HDAC repressor complexes to thepromoter DNA. During normal hematopoiesis, retinoic acid (RA) binds RARαand displaces the repressor complex, allowing expression of genesimplicated in myeloid differentiation. The RARα fusion proteinsoccurring in APL patients are no longer responsive to physiologicallevels of RA and they interfere with the expression of the RA-induciblegenes that promote myeloid differentiation. This results in a clonalexpansion of promyelocytic cells and development of leukaemia. In vitroexperiments have shown that TSA is capable of restoringRA-responsiveness to the fusion RARα proteins and of allowing myeloiddifferentiation. These results establish a link between HDACs andoncogenesis and suggest that HDACs are potential targets forpharmaceutical intervention in APL patients. (See, for example, Kitamuraet al., 2000; David et al., 1998; Lin et al., 1998).

Furthermore, different lines of evidence suggest that HDACs may beimportant therapeutic targets in other types of cancer. Cell linesderived from many different cancers (prostate, colorectal, breast,neuronal, hepatic) are induced to differentiate by HDAC inhibitors(Yoshida and Horinouchi, 1999). A number of HDAC inhibitors have beenstudied in animal models of cancer. They reduce tumour growth andprolong the lifespan of mice bearing different types of transplantedtumours, including melanoma, leukaemia, colon, lung and gastriccarcinomas, etc. (Ueda et al., 1994; Kim et al., 1999).

Psoriasis is a common chronic disfiguring skin disease which ischaracterised by well-demarcated, red, hardened scaly plaques: these maybe limited or widespread. The prevalence rate of psoriasis isapproximately 2%, i.e., 12.5 million sufferers in the triad countries(US/Europe/Japan). While the disease is rarely fatal, it clearly hasserious detrimental effects upon the quality of life of the patient:this is further compounded by the lack of effective therapies. Presenttreatments are either ineffective, cosmetically unacceptable, or possessundesired side effects. There is therefore a large unmet clinical needfor effective and safe drugs for this condition.

Psoriasis is a disease of complex etiology. Whilst there is clearly agenetic component, with a number of gene loci being involved, there arealso undefined environmental triggers. Whatever the ultimate cause ofpsoriasis, at the cellular level, it is characterised by local T-cellmediated inflammation, by keratinocyte hyperproliferation, and bylocalised angiogenesis. These are all processes in which histonedeacetylases have been implicated (see, e.g., Saunders et al., 1999;Bernhard et al, 1999; Takahashi et al, 1996; Kim et al, 2001). ThereforeHDAC inhibitors may be of use in therapy for psoriasis. Candidate drugsmay be screened, for example, using proliferation assays with T-cellsand/or keratinocytes.

Thus, one aim of the present invention is the provision of compoundswhich are potent inhibitors of histone deacetylases (HDACs). There is apressing need for such compounds, particularly for use asantiproliferatives, for example, anti-cancer agents, agents for thetreatment of psoriasis, etc.

Such molecules desirably have one or more of the following propertiesand/or effects:

-   -   (a) easily gain access to and act upon tumour cells;    -   (b) down-regulate HDAC activity;    -   (c) inhibit the formation of HDAC complexes;    -   (d) inhibit the interactions of HDAC complexes;    -   (e) inhibit tumour cell proliferation;    -   (e) promote tumour cell apoptosis;    -   (f) inhibit tumour growth; and,    -   (g) complement the activity of traditional chemotherapeutic        agents.

A number of carbamic acid compounds have been described.

Certain classes of carbamic acid compounds which inhibit HDAC aredescribed in Watkins et al., 2002a, 2002b, and 2002c.

Esters

Takahashi et al., 1992, describe several compounds of the followingformula, where n is 0, 1, or 2, which apparently have activity as ananti-ulcer agent (see page 6, right hand column; page 8, middle; tableon pages 10-12, compounds 6-12, 14, and 22-24).

Suzuki and Oya, 1974, and Fujii et al., 1982, describe the followingcompound (CAS Registry No. 52134-35-7), which apparently is used as anintermediate in the synthesis of derivatives of para-aminobenzoic acid.

Kompis and Wick, 1977, describe the following compound (CAS Registry No.65566-10-1), which apparently is used as an intermediate in thesynthesis of analogues of the bactericidal agent trimethoprim.

SUMMARY OF THE INVENTION

One aspect of the invention pertains to active carbamic acid compounds,as described herein.

Another aspect of the invention pertains to active compounds, asdescribed herein, which inhibit HDAC activity.

Another aspect of the invention pertains to active compounds, asdescribed herein, which treat conditions which are known to be mediatedby HDAC, or which are known to be treated by HDAC inhibitors (such as,e.g., trichostatin A).

Another aspect of the invention pertains to active compounds, asdescribed herein, which (a) regulate (e.g., inhibit) cell proliferation;(b) inhibit cell cycle progression; (c) promote apoptosis; or (d) acombination of one or more of these.

Another aspect of the invention pertains to active compounds, asdescribed herein, which are anti-HDAC agents, and which treat acondition mediated by HDAC.

Another aspect of the invention pertains to active compounds, asdescribed herein, which are anticancer agents, and which treat cancer.

Another aspect of the invention pertains to active compounds, asdescribed herein, which are antiproliferative agents, and which treat aproliferative condition.

Another aspect of the invention pertains to active compounds, asdescribed herein, which are antipsoriasis agents, and which treatpsoriasis.

Another aspect of the present invention pertains to a compositioncomprising a compound, as described herein, and a carrier.

Another aspect of the present invention pertains to a compositioncomprising a compound, as described herein, and a pharmaceuticallyacceptable carrier.

Another aspect of the present invention pertains to methods ofinhibiting HDAC in a cell, comprising contacting said cell with aneffective amount of an active compound, as described herein, whether invitro or in vivo.

Another aspect of the present invention pertains to methods of (a)regulating (e.g., inhibiting) cell proliferation; (b) inhibiting cellcycle progression; (c) promoting apoptosis; or (d) a combination of oneor more of these, comprising contacting a cell with an effective amountof an active compound, as described herein, whether in vitro or in vivo.

Another aspect of the present invention pertains to methods of treatinga condition which is known to be mediated by HDAC, or which is known tobe treated by HDAC inhibitors (such as, e.g., trichostatin A),comprising administering to a subject in need of treatment atherapeutically-effective amount of an active compound, as describedherein.

Another aspect of the present invention pertains to methods of treatingcancer, comprising administering to a subject in need of treatment atherapeutically-effective amount of an active compound, as describedherein.

Another aspect of the present invention pertains to methods of treatinga proliferative condition comprising administering to a subject in needof treatment a therapeutically-effective amount of an active compound,as described herein.

Another aspect of the present invention pertains to methods of treatingpsoriasis comprising administering to a subject in need of treatment atherapeutically-effective amount of an active compound, as describedherein.

Another aspect of the present invention pertains to an active compound,as described herein, for use in a method of treatment of the human oranimal body by therapy.

Another aspect of the present invention pertains to use of an activecompound, as described herein, for the manufacture of a medicament foruse in the treatment of a condition mediated by HDAC, a condition knownto be treated by HDAC inhibitors (such as, e.g., trichostatin A),cancer, a proliferative condition, psoriasis, or other condition asdescribed herein.

Another aspect of the present invention pertains to a kit comprising (a)the active compound, preferably provided as a pharmaceutical compositionand in a suitable container and/or with suitable packaging; and (b)instructions for use, for example, written instructions on how toadminister the active compound.

Another aspect of the present invention pertains to compounds obtainableby a method of synthesis as described herein, or a method comprising amethod of synthesis as described herein.

Another aspect of the present invention pertains to compounds obtainedby a method of synthesis as described herein, or a method comprising amethod of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates,as described herein, which are suitable for use in the methods ofsynthesis described herein.

Another aspect of the present invention pertains to the use of suchnovel intermediates, as described herein, in the methods of synthesisdescribed herein.

As will be appreciated by one of skill in the art, features andpreferred embodiments of one aspect of the invention will also pertainto other aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

In one aspect, the present invention pertains to carbamic acid compoundsof the formula:

wherein:

-   -   J is a linking functional group and is independently:        -   —O—C(═O)— or —C(═O)—O— or —C(═O)—;    -   Cy is a cyclyl group and is independently:        -   C₃₋₂₀carbocyclyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl;    -   and is optionally substituted;    -   Q¹ is a cyclyl leader group, and is independently a divalent        bidentate group obtained by removing two hydrogen atoms from a        ring carbon atom of a saturated monocyclic hydrocarbon having        from 4 to 7 ring atoms, or by removing two hydrogen atoms from a        ring carbon atom of saturated monocyclic heterocyclic compound        having from 4 to 7 ring atoms including 1 nitrogen ring atom or        1 oxygen ring atom; and is optionally substituted;    -   Q² is an acid leader group, and is independently:        -   C₁₋₈alkylene;        -   and is optionally substituted; or:    -   Q² is an acid leader group, and is independently:        -   C₅₋₂₀arylene;        -   C₅₋₂₀arylene-C₁₋₇alkylene;        -   C₁₋₇alkylene-C₅₋₂₀arylene; or,        -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene;        -   and is optionally substituted;            and pharmaceutically acceptable salts, solvates, amides,            esters, ethers, chemically protected forms, and prodrugs            thereof.

In preferred embodiments, the carbamic acid group, —C(═O)NHOH, isunmodified (e.g., is not an ester).

Note that each of the groups -Q¹-Cy and -Q²-C(═O)NHOH is a monovalentand monodentate species; and that is it not intended that these groupsbe linked, other than via the group J.

For the avoidance of doubt, it is not intended that the group, J, bepart of another functional group. For example, when J is a ketone group,it is not intended that is be part of an ester, an amide, a urea, acarbamate, a carbonate, etc. For example, when J is an ester group, itis not intended that it be part of a carbamate, a carbonate, etc. Q¹ andQ², and optional substituents thereon, are selected accordingly.

The Linking Functional Group, J

The linking functional group, J, is —O—C(═O)— or —C(═O)—O— or —C(═O)—.

In one embodiment, J is —O—C(═O)— or —C(═O)—O— (also referred to hereinas an “ester” group). Ester groups have a C atom, a carbonyl O atom, anda chain O atom.

In one embodiment, J is —O—C(═O)—(also referred to herein as a “reverseester group”).

In one embodiment, J is —C(═O)—O—(also referred to herein as a “forwardester group”).

In one embodiment, J is —C(═O)— (also referred to herein as a “ketone”group). Ketone groups have a C atom and a carbonyl O atom.

The Cyclyl Leader Group, Q¹

The cyclyl leader group, Q¹, is independently a divalent bidentate groupobtained by removing two hydrogen atoms from a ring carbon atom of asaturated monocyclic hydrocarbon having from 4 to 7 ring atoms, or byremoving two hydrogen atoms from a ring carbon atom of saturatedmonocyclic heterocyclic compound having from 4 to 7 ring atoms including1 nitrogen ring atom or 1 oxygen ring atom; and is optionallysubstituted.

In one embodiment, Q¹ is independently a group of the formula;

wherein:

-   the ring independently has from 4 to 7 ring atoms;-   Z is independently —CH₂—, —N(R^(N))— or —O—;-   R^(N), if present, is independently as defined below; and-   Q¹ is optionally further substituted.

In one embodiment, the ring independently has 4, 5, 6, or 7 ring atoms.

In one embodiment, the ring independently has 5, 6, or 7 ring atoms.

In one embodiment, the ring independently has 5 or 6 ring atoms.

In one embodiment, the ring independently has 5 ring atoms.

In one embodiment, the ring independently has 6 ring atoms.

In one embodiment, Z is independently —CH₂—, —N(R^(N))— or —O—.

In one embodiment, Z is independently —CH₂— or —N(R^(N))—.

In one embodiment, Z is independently —CH₂— or —O—;

In one embodiment, Z is independently —N(R^(N))— or —O—.

In one embodiment, Z is independently —CH₂—.

In one embodiment, Z is independently —N(R^(N))—.

In one embodiment, Z is independently —O—.

In one embodiment, the ring independently has 5 or 6 ring atoms; and Zis independently —CH₂— or —N(R^(N))—.

In one embodiment, Z is independently adjacent to the carbon atom whichlinks Cy and J.

In one embodiment, Q¹ is independently a group of the formula;

wherein:

-   y is independently 1, 2, 3, or 4;-   Z is as defined above; and,-   Q¹ is optionally further substituted.

Examples of such groups include:

In one embodiment, y is independently 1, 2, 3, or 4.

In one embodiment, y is independently 2, 3, or 4.

In one embodiment, y is independently 2 or 3.

In one embodiment, y is independently 2.

In one embodiment, y is independently 3.

In one embodiment, y is independently 2 or 3; and Z is independently—CH₂— or —N(R^(N))—.

In one embodiment, y is independently 2; and Z is independently —CH₂—.Examples of such groups include:

In one embodiment, y is independently 3; and Z is independently —CH₂—.Examples of such groups include:

In one embodiment, y is independently 3; and Z is independently—N(R^(N))—. Examples of such groups include:

The Nitrogen Substituent, R^(N)

The nitrogen substituent, R^(N), if present, is independently selectedfrom:

-   —H; C₁₋₇alkyl (including, e.g., C₅₋₂₀aryl-C₁₋₇alkyl);    C₃₋₂₀heterocyclyl; and C₅₋₂₀aryl.

In one embodiment, R^(N), if present, is independently selected from:

-   —H; C₁₋₇alkyl (including, e.g., C₅₋₂₀aryl-C₁₋₇alkyl); and C₅₋₂₀aryl.

In one embodiment, R^(N), if present, is independently selected from:

-   —H and C₁₋₇alkyl (including, e.g., C₅₋₂₀aryl-C₁₋₇alkyl).

In one embodiment, R^(N), if present, is independently selected from:

-   —H and C₅₋₂₀aryl.

In one embodiment, R^(N), if present, is independently selected from:—H,-Me, -Et, -Ph, and —CH₂-Ph.

In one embodiment, R^(N), if present is independently—H.

The Cyclyl Leader Group, Q¹: Substituents

In one embodiment, Q¹ is independently substituted or unsubstituted.

In one embodiment, Q¹ is independently substituted.

In one embodiment, Q¹ is independently unsubstituted.

Note that it is not intended that the nitrogen substituent, R^(N), ifpresent, be considered when determining if Q¹ is substituted orunsubstituted.

Examples of substituents on Q¹ include, but are not limited to, thosedescribed under the heading “Substituents” below.

Further examples of substituents Q¹ include, but are not limited to,those described under the heading “The Cyclyl Group, Cy: Substituents”below.

In one embodiment, substituents on Q¹, if present, are independentlyselected from: halo, hydroxy, ether (e.g., C₁₋₇alkoxy), C₅₋₂₀aryl, acyl,amino, amido, acylamido, and oxo. Where a substituent is on an arylenegroup (e.g., phenylene), it may additionally be selected from:C₁₋₇alkyl, including substituted C₁₋₇alkyl.

In one embodiment, substituents on Q¹, if present, are independentlyselected from:—F, —Cl, —Br, —I, —OH, —OMe, —OEt, —O(iPr), -Ph, —C(═O)Me,—NH₂, —NMe₂, —NEt₂, morpholino, —CONH₂, —CONMe₂, —NHCOMe, and ═O. Wherea substituent is on an arylene group (e.g., phenylene), it mayadditionally be selected from: -Me, -Et, -iPr, -tBu, —CF₃.

Assigning the Cyclyl Group, Cy

If, within the group -Q¹-Cy, there is a plurality of candidate groupssatisfying the definition of Cy (referred to as candidate Cy groups),then the candidate Cy group which is furthest from the C atom of thegroup, J, is identified as Cy (and referred to as “the relevant Cygroup”).

In this context, distance (e.g., further, furthest) is measured as thenumber of chain atoms in the shortest continuous chain linking thegroups (i.e., linking Cy with the C atom of the group J).

If there is a plurality of furthest candidate Cy groups, then the one(including any substituents) with the largest molecular weight is therelevant one.

If there is a plurality of furthest heaviest candidate Cy groups, thenthe one (excluding any substituents) with the most annular heteroatomsis the relevant one.

If there is a plurality of furthest heaviest candidate Cy groups withthe most annular heteroatoms, then the one with an IUPAC name whichalphabetically precedes the other(s), is the relevant one.

The Cyclyl Group, Cy

Cy is independently: C₃₋₂₀carbocyclyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl;and is optionally substituted.

Examples of substituents on Cy are discussed below.

The Cyclyl Group, Cy: Carbocyclyl

In one embodiment, Cy is independently C₃₋₂₀carbocyclyl; and isoptionally substituted.

In one embodiment, Cy is independently monocyclic C₃₋₇carbocyclyl, andis optionally substituted.

In one embodiment, Cy is independently monocyclic C₅₋₆carbocyclyl, andis optionally substituted.

In one embodiment, Cy is independently C₃₋₂₀carbocyclyl derived from oneof the following: cyclopropane, cyclobutane, cyclopentane, cyclohexane,cyclopentene, cyclohexene, norbornane, adamantane, cyclopentanone, andcyclohexanone; and is optionally substituted.

In one embodiment, Cy is independently an optionally substitutedcyclohexyl group of the formula:

wherein n is independently an integer from 0 to 11, and each R^(A) isindependently a substituent as defined herein (see under the heading“The Cyclyl Group, Cy: Substituents”).The Cyclyl Group, Cy: Heterocyclyl

In one embodiment, Cy is independently C₃₋₂₀heterocyclyl; and isoptionally substituted.

In one embodiment, Cy is independently monocyclic C₃₋₇heterocyclyl, andis optionally substituted.

In one embodiment, Cy is independently monocyclic C₅₋₆heterocyclyl, andis optionally substituted.

In one embodiment, Cy is independently C₃₋₂₀heterocyclyl derived fromone of the following: piperidine, azepine, tetrahydropyran, morpholine,azetidine, piperazine, imidazoline, piperazinedione, and oxazolinone;and is optionally substituted.

The Cyclyl Group, Cy: Aryl

In one embodiment, Cy is independently C₅₋₂₀aryl; and is optionallysubstituted.

In one embodiment, Cy is independently C₅₋₂₀carboaryl orC₅₋₂₀heteroaryl; and is optionally substituted.

In one embodiment, Cy is independently C₅₋₂₀heteroaryl; and isoptionally substituted. In one embodiment, Cy is monocyclicC₅₋₂₀heteroaryl; and is optionally substituted. In one embodiment, Cy ismonocyclic C₅₋₆heteroaryl; and is optionally substituted.

In one embodiment, Cy is independently C₅₋₂₀carboaryl; and is optionallysubstituted. In one embodiment, Cy is monocyclic C₅₋₂₀carboaryl; and isoptionally substituted. In one embodiment, Cy is monocyclicC₅₋₆carboaryl; and is optionally substituted. In one embodiment, Cy isphenyl; and is optionally substituted.

In one embodiment, Cy is independently C₅₋₂₀aryl derived from one of thefollowing: benzene, pyridine, furan, indole, pyrrole, imidazole,naphthalene, quinoline, benzimidazole, benzothiofuran, fluorene,acridine, and carbazole; and is optionally substituted.

In one embodiment, Cy is independently C₅₋₂₀aryl derived from benzeneand is optionally substituted.

The Cyclyl Group, Cy: Phenyl

In one embodiment, Cy is independently an optionally substituted phenylgroup of the formula:

wherein n is independently an integer from 0 to 5, and each R^(A) isindependently a substituent as defined herein (see under the heading“The Cyclyl Group, Cy: Substituents”).

In one embodiment, n is an integer from 0 to 5.

In one embodiment, n is an integer from 0 to 4.

In one embodiment, n is an integer from 0 to 3.

In one embodiment, n is an integer from 0 to 2.

In one embodiment, n is 0 or 1.

In one embodiment, n is an integer from 1 to 5.

In one embodiment, n is an integer from 1 to 4.

In one embodiment, n is an integer from 1 to 3.

In one embodiment, n is 1 or 2.

In one embodiment, n is 5.

In one embodiment, n is 4.

In one embodiment, n is 3.

In one embodiment, n is 2.

In one embodiment, n is 1.

In one embodiment, n is 0.

If the phenyl group has less than the full complement of ringsubstituents, R^(A), they may be arranged in any combination. Forexample, if n is 1, R^(A) may be in the 2′-, 3′-, 4′-, 5′-, or6′-position. Similarly, if n is 2, the two R^(A) groups may be in, forexample, the 2′,3′-, 2′,4′-, 2′,5′-, 2′,6′-, 3′,4′-, or 3′,5′-positions.If n is 3, the three R^(A) groups may be in, for example, the 2′,3′,4′-,2′,3′,5′-, 2′,3′,6′-, or 3′,4′,5′-positions.

In one embodiment, n is 0.

In one embodiment, n is 1, and the R^(A) group is in the 4′-position.

In one embodiment, n is 2, and one R^(A) group is in the 4′-position,and the other R^(A) group is in the 2′-position.

In one embodiment, n is 2, and one R^(A) group is in the 4′-position,and the other R^(A) group is in the 3′-position.

The Cyclyl Group, Cy: Substituents

Examples of substituents on Cy (e.g., R^(A)), include, but are notlimited to, those described under the heading “Substituents” below.

Further examples of substituents on Cy (e.g., R^(A)), include, but arenot limited to, those described below.

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

-   (1) ester;-   (2) amido;-   (3) acyl;-   (4) halo;-   (5) hydroxy;-   (6) ether;-   (7) C₁₋₇alkyl, including substituted C₁₋₇alkyl;-   (8) C₅₋₂₀aryl, including substituted C₅₋₂₀aryl;-   (9) sulfonyl;-   (10) sulfonamido.

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

-   (1)—C(═O)OR¹, wherein R¹ is independently C₁₋₇alkyl as defined in    (7);-   (2)—C(═O)NR²R³, wherein each of R² and R³ is independently—H or    C₁₋₇alkyl as defined in (7);-   (3)—C(═O)R⁴, wherein R⁴ is independently C₁₋₇alkyl as defined in (7)    or C₅₋₂₀aryl as defined in (8);-   (4)—F, —Cl, —Br, —I;-   (5)—OH;-   (6)—OR⁵, wherein R⁵ is independently C₁₋₇alkyl as defined in (7) or    C₅₋₂₀aryl as defined in-   (8);-   (7) C₁₋₇alkyl, including substituted C₁₋₇alkyl, e.g.,    -   halo-C₁₋₇alkyl;    -   amino-C₁₋₇alkyl (e.g., —(CH₂)_(w)-amino);    -   carboxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—COOH);    -   hydroxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—OH);    -   C₁₋₇alkoxy-C₁₋₇alkyl (e.g., —(CH₂)_(w)—O—C₁₋₇alkyl);    -   C₅₋₂₀aryl-C₁₋₇alkyl;    -   wherein w is 1, 2, 3, or 4;-   (8) C₅₋₂₀aryl, including substituted C₅₋₂₀aryl;-   (9)—SO₂R⁷, wherein R⁷ is independently C₁₋₇alkyl as defined in (7)    or C₅₋₂₀aryl as defined in (8);-   (10)—SO₂NR⁸R⁹, wherein each of R⁸ and R⁹ is independently—H or    C₁₋₇alkyl as defined in (7);

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

-   (1)—C(═O)OMe, —C(═O)OEt, —C(═O)O(Pr), —C(═OC)O(iPr), —C(═O)O(nBu),    —C(═O)O(sBu), —C(═O)O(iBu), —C(═O)O(tBu), —C(═O)O(nPe);-   —C(═O)OCH₂CH₂OH, —C(═O)OCH₂CH₂OMe, —C(═O)OCH₂CH₂OEt;-   (2)—(C═O)NH₂, —(C═O)NMe₂, —(C═O)NEt₂, —(C═O)N(iPr)₂,    —(C═O)N(CH₂CH₂OH)₂;-   (3)—(C═O)Me, —(C═O)Et, —(C═O)-cHex, —(C═O)Ph;-   (4)—F, —Cl, —Br, —I;-   (5)—OH;-   (6)—OMe, —OEt, —O(iPr), —O(tBu), —OPh;-   —OCF₃, —OCH₂CF₃;-   —OCH₂CH₂OH, —OCH₂CH₂OMe, —OCH₂CH₂OEt;-   —OCH₂CH₂NH₂, —OCH₂CH₂NMe₂, —OCH₂CH₂N(iPr)₂;-   —OPh, —OPh—Me, —OPh—OH, —OPh—OMe, O—Ph—F, —OPh—Cl, —OPh—Br, —OPh-I;-   (7)—Me, —Et,-nPr, -iPr,-nBu, -iBu, -sBu, -tBu, -nPe;-   —CF₃, —CH₂CF₃;-   —CH₂CH₂OH, —CH₂CH₂OMe, —CH₂CH₂OEt;-   —CH₂CH₂NH₂, —CH₂CH₂NMe₂, —CH₂CH₂N(iPr)₂;-   —CH₂-Ph;-   (8) —Ph, —Ph—-Me, —Ph—OH, —Ph—OMe, —Ph—F, —Ph—Cl, —Ph—Br, —Ph—I;-   (9)—SO₂Me, —SO₂Et, —SO₂Ph;-   (10)—SO₂NH₂, —SO₂NMe₂, —SO₂NEt₂.

In one embodiment, each of the substituents on Cy (e.g., each R^(A)), isindependently selected from:

-   —C(═O)OMe, —OMe, —C(═O)Me, —SO₂Me, —SO₂NMe₂, —C(═O)NH₂, —OCF₃,    and—CH₂CH₂OH.    The Acid Leader Group, Q²

The acid leader group, Q², is independently:

-   -   C₁₋₈alkylene;    -   and is optionally substituted; or:    -   C₅₋₂₀arylene;    -   C₅₋₂₀arylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene; or,    -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene;    -   and is optionally substituted;

In one embodiment, the acid leader group, Q², is independently:

-   -   C₁₋₈alkylene;    -   and is optionally substituted;

In one embodiment, the acid leader group, Q², is independently:

-   -   C₅₋₂₀arylene;    -   C₅₋₂₀arylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene; or,    -   and is optionally substituted;

In one embodiment, the acid leader group, Q², is independently:

-   -   C₅₋₂₀arylene;    -   and is optionally substituted;

In one embodiment, the acid leader group, Q², is independently:

C₅₋₂₀arylene-C₁₋₇alkylene;

-   -   C₁₋₇alkylene-C₅₋₂₀arylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene; or,    -   and is optionally substituted;

Again, for the avoidance of doubt, it is not intended that the group, J,be part of another functional group. Q¹ and Q², and optionalsubstituents thereon, are selected accordingly.

The Acid Leader Group, Q²: Backbone Length

The acid leader group, Q², has a backbone length, as determined by thenumber of chain atoms in the shortest continuous chain of atoms linkingJ and the carbamic acid group, —C(═O)NHOH.

If Q² is alkylene, Q² necessarily has a backbone of at least 1 atom.Some examples are shown below.

If Q² is arylene, arylene-alkylene, alkylene-arylene,alkylene-arylene-alkylene, Q² necessarily has a backbone of at least 2atoms. Some examples are shown below.

Without wishing to be bound to any particular theory, it is believedthat Q² groups with shorter backbone lengths prevent or reduce theinteraction of the carbamic acid group (—C(═O)NHOH) with HDAC (or itscomplexes), and thereby reduce the compound's activity as an HDACinhibitor.

In one embodiment, Q² independently has a backbone of at least 3 atoms.

In one embodiment, Q² independently has a backbone of at least 4 atoms.

In one embodiment, Q² independently has a backbone of at least 5 atoms.

In one embodiment, Q² independently has a backbone of at least 6 atoms.

In one embodiment, Q² independently has a backbone of:

-   from 3 to 8 atoms;-   from 3 to 7 atoms;-   from 3 to 6 atoms; or,-   from 3 to 5 atoms.

In one embodiment, Q² independently has a backbone of:

-   from 4 to 8 atoms;-   from 4 to 7 atoms;-   from 4 to 6 atoms; or,-   from 4 to 5 atoms.

In one embodiment, Q² independently has a backbone of:

-   from 5 to 8 atoms; or-   from 5 to 7 atoms; or-   from 5 to 6 atoms.

In one embodiment, Q² independently has a backbone of from 5 to 6 atoms.

In one embodiment, Q² independently has a backbone of 3 atoms.

In one embodiment, Q² independently has a backbone of 4 atoms.

In one embodiment, Q² independently has a backbone of 5 atoms.

In one embodiment, Q² independently has a backbone of 6 atoms.

In one embodiment, Q² independently has a backbone of 7 atoms.

In one embodiment, Q² independently has a backbone of 7 atoms.

In one embodiment, the Q² backbone is independently a carbon backbone.

In one embodiment, the backbone of “atoms” is a backbone of “carbonatoms.”

Note that, for embodiments which are characterised by, or furthercharacterised by, a backbone length limitation, corresponding changes inthe description of that embodiment may be implicit. For example, for anembodiment wherein (a) Q² is a partially unsaturated C₂₋₈alkylene groupand (b) Q² has a backbone of 4 carbon atoms, the term “C₂₋₈alkylene”group is necessarily, and implicitly, interpreted as “C₄₋₈alkylene.”

The Acid Leader Group, Q²: Substitution

In one embodiment, Q² is independently unsubstituted or substituted.

In one embodiment, Q² is independently substituted.

In one embodiment, Q² is independently unsubstituted.

The backbone atoms of the acid leader group, Q², which link J and thecarbamic acid group (—C(═O)NHOH), are denoted α, β, γ, δ, etc., startingwith the backbone atom adjacent to the carbamic acid group. Someexamples are illustrated below.

Without wishing to be bound to any particular theory, it is believedthat groups (e.g., substituents), particularly bulky groups (e.g.,substituents), at the α-position, or at either or both of the α- andβ-positions, prevent or reduce the interaction of the carbamic acidgroup (—C(═O)NHOH) with HDAC (or its complexes), and thereby reduce thecompound's activity as an HDAC inhibitor.

In one embodiment, Q² is, additionally, unsubstituted at the α-position.

In one embodiment, Q² is, additionally, unsubstituted at the α-positionand unsubstituted at the β-position.

Note that, in some embodiments, Q² may have a non-linear alkylene group(for example, a branched alkylene) adjacent to the carbamic acid group.An example, wherein Q² is a branched saturated C₆-alkylene, having amethyl group at the α-position, is shown below. Although there is agroup (i.e., a methyl group) at the α-position, such compounds are“unsubstituted” at the α-position, because the α-methyl group itself isconsidered to be part of the unsubstituted Q². Another example, whereinQ² is a branched saturated C₆-alkylene, having an amino group at theα-position and a methyl group at the α-position, is shown below; suchcompounds are “α-substituted, β-unsubstituted.”

In one embodiment, in which Q² is a group as defined herein (e.g.,C₁₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group:

-   (a) Q² is, additionally, unsubstituted at the α-position and/or:-   (b) that adjacent alkylene group has a—CH₂— or ═CH— group adjacent    to the carbamic acid group (that is, at the α-position) and/or:-   (c) that adjacent alkylene group has a—CH₂— group adjacent to the    carbamic acid group (that is, at the α-position) and/or:-   (d) that adjacent alkylene group has a ═CH— group adjacent to the    carbamic acid group (that is, at the α-position).

In one embodiment, in which Q² is a group as defined herein (e.g.,C₁₋₈alkylene, C₅₋₂₀arylene-C₁₋₇alkylene,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene) having an alkylene groupadjacent to the carbamic acid group:

-   (a) Q² is, additionally, unsubstituted at the α-position and    unsubstituted at the β-position and/or:-   (b) that adjacent alkylene group has a—CH₂CH₂—, —CH═CH—, or —C C—    group adjacent to the carbamic acid group (that is, at the    α,β-position) and/or:-   (c) that adjacent alkylene group has a—CH₂CH₂— or —CH═CH— group    adjacent to the carbamic acid group (that is, at the α,β-position)    and/or:-   (d) that adjacent alkylene group has a—CH₂CH₂— group adjacent to the    carbamic acid group (that is, at the α,β-position) and/or:-   (e) that adjacent alkylene group has a—CH═CH— group adjacent to the    carbamic acid group (that is, at the α,β-position).

Again, for the avoidance of doubt, it is not intended that the group, J,be part of another functional group. Q1 and Q², and optionalsubstituents thereon, are selected accordingly.

The Acid Leader Group. Q²: Substituents

In one embodiment, Q² is independently substituted or unsubstituted.

In one embodiment, Q² is independently substituted.

In one embodiment, Q² is independently unsubstituted.

Examples of substituents on Q² (e.g., R^(B)), include, but are notlimited to, those described under the heading “Substituents” below.

Further examples of substituents Q² (e.g., R^(B)), include, but are notlimited to, those described under the heading “The Cyclyl Group, Cy:Substituents” above.

In one embodiment, substituents on Q² (e.g., R^(B)), if present, areindependently selected from: halo, hydroxy, ether (e.g., C₁₋₇alkoxy),C₅₋₂₀aryl, acyl, amino, amido, acylamido, nitro, and oxo. Where asubstituent is on an arylene group (e.g., phenylene), it mayadditionally be selected from: C₁₋₇alkyl, including substitutedC₁₋₇alkyl.

In one embodiment, substituents on Q² (e.g., R^(B)), if present, areindependently selected from:—F, —Cl, —Br, —I, —OH, —OMe, —OEt, —O(iPr),—Ph, —C(═O)Me, —NH₂, —NMe₂, —NEt₂, morpholino, —CONH₂, —CONMe₂, —NHCOMe,—NO₂, and ═O. Where a substituent is on an arylene group (e.g.,phenylene), it may additionally be selected from: -Me, -Et, -iPr, -tBu,—CF₃.

The Acid Leader Group, Q²: Alkylene

In one embodiment, the acid leader group, Q², is independentlyC₁₋₈alkylene, and is optionally substituted.

In one embodiment, Q² is independently:

-   (a) a saturated C₁₋₇alkylene group; or:-   (b) a partially unsaturated C₂₋₇alkylene group; or:-   (c) an aliphatic C₁₋₇alkylene group; or:-   (d) a linear C₁₋₇alkylene group; or:-   (e) a branched C₂₋₇alkylene group; or:-   (f) a saturated aliphatic C₁₋₇alkylene group; or-   (g) a saturated linear C₁₋₇alkylene group; or:-   (h) a saturated branched C₂₋₇alkylene group; or:-   (i) a partially unsaturated aliphatic C₂₋₇alkylene group; or:-   (j) a partially unsaturated linear C₂₋₇alkylene group; or:-   (k) a partially unsaturated branched C₂₋₇alkylene group;    and is optionally substituted.

In one embodiment, Q² additionally has a backbone length as describedabove under the heading “The Acid Leader Group, Q²: Backbone Length.”

Note that, for embodiments excluding, e.g., certain backbone lengths,absence of adjacent carbon-carbon double bonds, etc., it is to beunderstood that the corresponding species listed below are similarlyexcluded from the respective embodiments discussed below.

In one embodiment, Q² is independently selected from:

-   -   —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,        —(CH₂)₇—, —(CH₂)₈—;    -   —CH(CH₃)—;    -   —CH(CH₃)CH₂—, —CH₂CH(CH₃)—;    -   —CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—;    -   —CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH(CH₃)CH₂—,        —CH₂CH₂CH₂CH(CH₃)—;    -   —CH(CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂CH₂—,        —CH₂CH₂CH(CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₃)CH₂—,        —CH₂CH₂CH₂CH₂CH(CH₃)—, —CH(CH₃)CH₂CH₂CH₂CH(CH₃)—;    -   —CH(CH₂CH₃)—;    -   —CH(CH₂CH₃)CH₂—, —CH₂CH(CH₂CH₃)—;    -   —CH(CH₂CH₃)CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂—, —CH₂CH₂CH(CH₂CH₃)—;        —CH(CH₂CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂—,    -   —CH₂CH₂CH(CH₂CH₃)CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)—;        —CH(CH₂CH₃)CH₂CH₂CH₂CH₂—, —CH₂CH(CH₂CH₃)CH₂CH₂CH₂—,        —CH₂CH₂CH(CH₂CH₃)CH₂CH₂—, —CH₂CH₂CH₂CH(CH₂CH₃)CH₂—,        —CH₂CH₂CH₂CH₂CH(CH₂CH₃)—;    -   —CH═CH—;    -   —CH═CHCH₂—, —CH₂CH═CH—;    -   —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—;    -   —CH═CHCH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂—, —CH₂CH₂CH═CHCH₂—,        —CH₂CH₂CH₂CH═CH—;    -   —CH═CHCH₂CH₂CH₂CH₂—, —CH₂CH═CHCH₂CH₂CH₂—, —CH₂CH₂CH═CHCH₂CH₂—,        —CH₂CH₂CH₂CH═CHCH₂—, —CH₂CH₂CH₂CH₂CH═CH—;    -   —C(CH₃)═CH—, —CH═C(CH₃)—;    -   —C(CH₃)═CHCH₂—, —CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—;    -   —CH(CH₃)CH═CH—, —CH₂C(CH₃)═CH—, —CH₂CH═C(CH₃)—;    -   —CH═CHCH═CH—;    -   —CH═CHCH═CHCH₂—, —CH₂CH═CHCH═CH—, —CH═CHCH₂CH═CH—;    -   —CH═CHCH═CHCH₂CH₂—, —CH═CHCH₂CH═CHCH₂—, —CH═CHCH₂CH₂CH═CH—,        —CH₂CH═CHCH═CHCH₂—, —CH₂CH═CHCH₂CH═CH—, —CH₂CH₂CH═CHCH═CH—;    -   —C(CH₃)═CHCH═CH—, —CH═C(CH₃)CH═CH—, —CH═CHC(CH₃)═CH—,        —CH═CHCH═C(CH₃)—;    -   —C C—;    -   —C CCH₂—, —CH₂C C—;—C CCH(CH₃)—, —CH(CH₃)C C—;    -   —C CCH₂CH₂—, —CH₂C CCH₂—, —CH₂CH₂C C—;    -   —C CCH(CH₃)CH₂—, —C CCH₂CH(CH₃)—;    -   —CH(CH₃)C CCH₂—, —CH₂C CCH(CH₃)—;    -   —CH(CH₃)CH₂C C—, —CH₂CH(CH₃)C C—;    -   —C CCH═CH—, —CH═CHC C—, —C CC C—;    -   —C CCH₂CH₂CH₂—, —CH₂CH₂CH₂C C—;    -   —C CCH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂C C—;    -   —C CCH═CHCH═CH—, —CH═CHC C—CH═CH—, —CH═CHCH═CHC C—;    -   —C(CH₃)═CHC C—, —CH═C(CH₃)C C—, —C CC(CH₃)═CH—, —C CCH═C(CH₃)—    -   cyclopentylene cyclopentenylene;    -   cyclohexylene, cyclohexenylene, cyclohexadienylene;

In one preferred embodiment, Q² is independently selected from:

-   -   —(CH₂)₅—;    -   —(CH₂)₆—;    -   —(CH₂)₇—;    -   —(CH₂)₈—;    -   —CH(CH₃)CH₂CH₂CH₂CH₂—;    -   —CH₂CH₂CH₂CH₂CH(CH₃)—;    -   —CH₂CH₂CH(CH₃)CH₂CH₂—;    -   —CH(CH₃)CH₂CH₂CH₂CH(CH₃)—;    -   —CH₂CH₂CH₂CH═CH—;    -   —CH₂CH₂CH₂CH₂CH═CH—;

In one preferred embodiment, Q² is independently selected from:

-   -   —(CH₂)₅—;    -   —(CH₂)₆—;    -   —(CH₂)₇—;    -   —(CH₂)₈—;    -   —CH(CH₃)CH₂CH₂CH₂CH₂—;    -   —CH₂CH₂CH₂CH₂CH(CH₃)—;    -   —CH₂CH₂CH₂CH═CH—; and,    -   —CH₂CH₂CH₂CH₂CH═CH—.

In one preferred embodiment, Q² is independently selected from:

-   -   —(CH₂)₅—;    -   —(CH₂)₆—;    -   —(CH₂)₇—; and    -   —(CH₂)₈—.        The Acid Leader Group, Q²: Arylene

In one embodiment, the acid leader group, Q², is independentlyC₅₋₂₀arylene, and is optionally substituted.

In one embodiment, Q² is independently C₅₋₂₀arylene; and is optionallysubstituted.

In one embodiment, Q² is independently C₅₋₆arylene; and is optionallysubstituted.

In one embodiment, Q² is independently phenylene; and is optionallysubstituted.

In one embodiment, Q² additionally has a backbone length as describedabove under the heading “The Acid Leader Group, Q²: Backbone Length.”

The Acid Leader Group, Q²:

Alkylene-Arylene, Arylene-Alkylene, and Alkylene-Arylene-Alkylene

In one preferred embodiment, the acid leader group, Q², isindependently:

-   -   C₅₋₂₀arylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-C₅₋₂₀arylene; or,    -   C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene;    -   and is optionally substituted.

In one preferred embodiment, Q² is independently:

-   -   C₅₋₆arylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-C₅₋₆arylene; or,    -   C₁₋₇alkylene-C₅₋₆arylene-C₁₋₇alkylene;    -   and is optionally substituted.

In one preferred embodiment, Q² is independently:

-   -   phenylene-C₁₋₇alkylene;    -   C₁₋₇alkylene-phenylene; or,    -   C₁₋₇alkylene-phenylene-C₁₋₇alkylene;    -   and is optionally substituted.

In one embodiment, Q² is independently C₁₋₇alkylene-C₅₋₂₀arylene; and isoptionally substituted.

In one embodiment, Q² is independently C₁₋₇alkylene-C₅₋₆arylene; and isoptionally substituted.

In one embodiment, Q² is independently C₁₋₇alkylene-phenylene; and isoptionally substituted.

In one embodiment, Q² is independently C₅₋₂₀arylene-C₁₋₇alkylene; and isoptionally substituted.

In one embodiment, Q² is independently C₅₋₂₀arylene-C₁₋₇alkylene; and isoptionally substituted.

In one embodiment, Q² is independently phenylene-C₁₋₇alkylene; and isoptionally substituted.

In one embodiment, Q² is independentlyC₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene; and is optionally substituted.

In one embodiment, Q² is independentlyC₁₋₇alkylene-C₅₋₆arylene-C₁₋₇alkylene; and is optionally substituted.

In one embodiment, Q² is independentlyC₁₋₇alkylene-phenylene-C₁₋₇alkylene; and is optionally substituted.

In one embodiment, in the above arylene-alkylene, alkylene-arylene, andalkylene-arylene-alkylene groups, each alkylene group is independently:

-   (a) a saturated C₁₋₇alkylene group; or:-   (b) a partially unsaturated C₂₋₇alkylene group; or:-   (c) an aliphatic C₁₋₇alkylene group; or:-   (d) a linear C₁₋₇alkylene group; or:-   (e) a branched C₂₋₇alkylene group; or:-   (f) a saturated aliphatic C₁₋₇alkylene group; or:-   (g) a saturated linear C₁₋₇alkylene group; or:-   (h) a saturated branched C₂₋₇alkylene group; or:-   (i) a partially unsaturated aliphatic C₂₋₇alkylene group; or:-   (j) a partially unsaturated linear C₂₋₇alkylene group; or:-   (k) a partially unsaturated branched C₂₋₇alkylene group;    and is optionally substituted.

In one embodiment, Q² additionally has a backbone length as describedabove under the heading “The Acid Leader Group, Q²: Backbone Length.”

In one embodiment, in the above arylene-alkylene, alkylene-arylene, andalkylene-arylene-alkylene groups, each alkylene group is independentlyselected from:

-   -   —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,    -   —CH₂—CH═CH—; and,    -   —CH₂—CH═CH—CH═CH—.

In one embodiment, each alkylene group is independently selected from:

-   -   —CH₂—, —CH₂CH₂—, and—CH₂—CH═CH—.

In one embodiment, each alkylene group is independently selected from:

—CH₂— and—CH₂CH₂—.

Again, for the avoidance of doubt, it is not intended that the group, J,be part of another functional group. Q², and optional substituentsthereon, are selected accordingly.

The Acid Leader Group, Q²: Certain Phenylene-Containing Embodiments

In one embodiment, Q² is independently:

-   -   phenylene;    -   and is optionally substituted.

In one embodiment, Q² is independently:

-   -   methylene-phenylene;    -   ethylene-phenylene;    -   and is optionally substituted.

In one embodiment, Q² is independently:

-   -   phenylene-methylene;    -   phenylene-ethylene; or,    -   phenylene-ethenylene (also known as phenylene-vinylene);    -   and is optionally substituted.

In one embodiment, Q² is independently methylene-phenylene; and isoptionally substituted (wherein R^(a) and m are as defined below):

In one embodiment, Q² is independently unsubstitutedmethylene-phenylene:

In one embodiment, Q² is independently:

-   -   methylene-phenylene-methylene;    -   methylene-phenylene-ethylene;    -   methylene-phenylene-ethenylene;    -   ethylene-phenylene-methylene;    -   ethylene-phenylene-ethylene;    -   ethylene-phenylene-ethenylene;    -   and is optionally substituted.

In the above phenylene, phenylene-alkylene, alkylene-phenylene, andalkylene-phenylene-alkylene groups, the phenylene linkage may be ortho(i.e., 1,2-), meta (i.e., 1,3-), or para (i.e., 1,4-), and the phenylenegroup is optionally substituted with from 1 to 4 substituents, R^(B):

In one embodiment, the phenylene linkage is meta or para.

In one embodiment, the phenylene linkage is meta.

In one embodiment, the phenylene linkage is para.

In one embodiment, m is an integer from 0 to 4.

In one embodiment, m is an integer from 0 to 3.

In one embodiment, m is an integer from 0 to 2.

In one embodiment, m is 0 or 1.

In one embodiment, m is an integer from 1 to 4.

In one embodiment, m is an integer from 1 to 3.

In one embodiment, m is 1 or 2.

In one embodiment, m is 4.

In one embodiment, m is 3.

In one embodiment, m is 2.

In one embodiment, m is 1.

In one embodiment, m is 0.

Each substituent, R^(B), is independently as defined above under theheading “The Acid Leader Group, Q²: Substituents.”

In one embodiment, the phenylene group is substituted or unsubstituted.

In one embodiment, the phenylene group is substituted.

In one embodiment, the phenylene group is unsubstituted.

Examples of Specific Embodiments: Esters

In one preferred embodiment:

J is—C(═O)O— (“forward ester”);

-   -   Q¹ is as defined above;    -   Q² is unsubstituted para-phenylene; and,    -   Cy is optionally substituted phenyl, as defined above.

Some individual embodiments of the present invention include thefollowing compounds.

1

PX118478 2

PX118479 3

PX118480 4

PX119101 5

PX118925 6

PX118926 7

PX118959 8

PX118966 9

PX119058 10

PX119059 11

PX119061 12

PX119062 13

PX119064 14

PX119065 15

PX119084 16

PX119100 17

PX119063 18

PX119085 19

PX119086 20

PX119102 21

PX119103Examples of Specific Embodiments: Ketones

In one preferred embodiment:

-   -   J is—C(═O)— (“ketone”);    -   Q¹ is as defined above;    -   Q² is unsubstituted para-methylene-phenylene; and, Cy is        optionally substituted phenyl, as defined above.

Some individual embodiments of the present invention include thefollowing compounds.

1

2

3

Chemical Terms

The term “carbo,” “carbyl,” “hydrocarbon” and “hydrocarbyl,” as usedherein, pertain to compounds and/or groups which have only carbon andhydrogen atoms (but see “carbocyclic” below).

The term “hetero,” as used herein, pertains to compounds and/or groupswhich have at least one heteroatom, for example, multivalent heteroatoms(which are also suitable as ring heteroatoms) such as boron, silicon,nitrogen, phosphorus, oxygen, sulfur, and selenium (more commonlynitrogen, oxygen, and sulfur) and monovalent heteroatoms, such asfluorine, chlorine, bromine, and iodine.

The term “saturated,” as used herein, pertains to compounds and/orgroups which do not have any carbon-carbon double bonds or carbon-carbontriple bonds.

The term “unsaturated,” as used herein, pertains to compounds and/orgroups which have at least one carbon-carbon double bond orcarbon-carbon triple bond.

The term “aliphatic,” as used herein, pertains to compounds and/orgroups which are linear or branched, but not cyclic (also known as“acyclic” or “open-chain” groups).

The term “ring,” as used herein, pertains to a closed ring of from 3 to10 covalently linked atoms, more preferably 3 to 8 covalently linkedatoms, yet more preferably 5 to 6 covalently linked atoms. A ring may bean alicyclic ring or an aromatic ring. The term “alicyclic ring,” asused herein, pertains to a ring which is not an aromatic ring.

The term “carbocyclic ring,” as used herein, pertains to a ring whereinall of the ring atoms are carbon atoms.

The term “carboaromatic ring,” as used herein, pertains to an aromaticring wherein all of the ring atoms are carbon atoms.

The term “heterocyclic ring,” as used herein, pertains to a ring whereinat least one of the ring atoms is a multivalent ring heteroatom, forexample, nitrogen, phosphorus, silicon, oxygen, or sulfur, though morecommonly nitrogen, oxygen, or sulfur. Preferably, the heterocyclic ringhas from 1 to 4 heteroatoms.

The term “cyclic compound,” as used herein, pertains to a compound whichhas at least one ring. The term “cyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a cyclic compound.

Where a cyclic compound has two or more rings, they may be fused (e.g.,as in naphthalene), bridged (e.g., as in norbornane), spiro (e.g., as inspiro[3.3]heptane), or a combination thereof. Cyclic compounds with onering may be referred to as “monocyclic” or “mononuclear,” whereas cycliccompounds with two or more rings may be referred to as “polycyclic” or“polynuclear.”

The term “carbocyclic compound,” as used herein, pertains to a cycliccompound which has only carbocyclic ring(s).

The term “heterocyclic compound,” as used herein, pertains to a cycliccompound which has at least one heterocyclic ring.

The term “aromatic compound,” as used herein, pertains to a cycliccompound which has at least one aromatic ring.

The term “carboaromatic compound,” as used herein, pertains to a cycliccompound which has only carboaromatic ring(s).

The term “heteroaromatic compound,” as used herein, pertains to a cycliccompound which has at least one heteroaromatic ring.

The term “monodentate substituents,” as used herein, pertains tosubstituents which have one point of covalent attachment.

The term “monovalent monodentate substituents,” as used herein, pertainsto substituents which have one point of covalent attachment, via asingle bond. Examples of such substituents include halo, hydroxy, andalkyl.

The term “multivalent monodentate substituents,” as used herein,pertains to substituents which have one point of covalent attachment,but through a double bond or triple bond. Examples of such substituentsinclude oxo, imino, alkylidene, and alklidyne.

The term “bidentate substituents,” as used herein, pertains tosubstituents which have two points of covalent attachment, and which actas a linking group between two other moieties. Examples of suchsubstituents include alkylene and arylene.

Substituents

The phrase “optionally substituted,” as used herein, pertains to aparent group which may be unsubstituted or which may be substituted.

Unless otherwise specified, the term “substituted,” as used herein,pertains to a parent group which bears one or more substituents. Theterm “substituent” is used herein in the conventional sense and refersto a chemical moiety which is covalently attached to, appended to, or ifappropriate, fused to, a parent group. A wide variety of substituentsare well known, and methods for their formation and introduction into avariety of parent groups are also well known.

The substituents are described in more detail below.

Alkyl: The term “alkyl,” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from a carbon atom of a hydrocarboncompound having from 1 to 20 carbon atoms (unless otherwise specified),which may be aliphatic or alicyclic, and which may be saturated,partially unsaturated, or fully unsaturated. Thus, the term “alkyl”includes the sub-classes alkenyl, alkynyl, cycloalkyl, etc., discussedbelow.

In this context, the prefixes (e.g., C₁₋₄, C₁₋₇, C₁₋₂₀, C₂₋₇, C₃₋₇,etc.) denote the number of carbon atoms, or range of number of carbonatoms. For example, the term “C₁₋₄alkyl,” as used herein, pertains to analkyl group having from 1 to 4 carbon atoms. Examples of groups of alkylgroups include C₁₋₄alkyl (“lower alkyl”), C₁₋₇alkyl, and C₁₋₂₀alkyl.

Examples of (unsubstituted) saturated alkyl groups include, but are notlimited to, methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl(C₅), hexyl (C₆), heptyl (C₇), octyl (C₈), nonyl (C₉), decyl (C₁₀),undecyl (C₁₁), dodecyl (C₁₂), tridecyl (C₁₃), tetradecyl (C₁₄),pentadecyl (C₁₅), and eicodecyl (C₂₀).

Examples of (unsubstituted) saturated linear alkyl groups include, butare not limited to, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl(C₄), n-pentyl (amyl) (C₅), n-hexyl (C₆), and n-heptyl (C₇).

Examples of (unsubstituted) saturated branched alkyl groups includeiso-propyl (C₃), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄),iso-pentyl (C₅), and neo-pentyl (C₅).

Cycloalkyl: The term “cycloalkyl,” as used herein, pertains to an alkylgroup which is also a cyclyl group; that is, a monovalent moietyobtained by removing a hydrogen atom from an alicyclic ring atom of acyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 20ring atoms (unless otherwise specified). Preferably, each ring has from3 to 7 ring atoms.

Examples of (unsubstituted) saturated cylcoalkyl groups include, but arenot limited to, those derived from: cyclopropane (C₃), cyclobutane (C₄),cyclopentane (C₅), cyclohexane (C₆), cycloheptane (C₇), norbornane (C₇),norpinane (C₇), norcarane (C₇), adamantane (C₁₀), and decalin(decahydronaphthalene) (C₁₀).

Examples of (substituted) saturated cycloalkyl groups, which are alsoreferred to herein as “alkyl-cycloalkyl” groups, include, but are notlimited to, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl,dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl,methylcyclohexyl, and dimethylcyclohexyl, menthane, thujane, carane,pinane, bornane, norcarane, and camphene.

Examples of (substituted) unsaturated cyclic alkenyl groups, which arealso referred to herein as “alkyl-cycloalkenyl” groups, include, but arenot limited to, methylcyclopropenyl, dimethylcyclopropenyl,methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl,dimethylcyclopentenyl, methylcyclohexenyl, and dimethylcyclohexenyl.

Examples of (substituted) cycloalkyl groups, with one or more otherrings fused to the parent cycloalkyl group, include, but are not limitedto, those derived from: indene (C₉), indan (e.g., 2,3-dihydro-1H-indene)(C₉), tetraline (1,2,3,4-tetrahydronaphthalene (C₁₀), acenaphthene(C₁₂), fluorene (C₁₃), phenalene (C₁₃), acephenanthrene (C₁₅),aceanthrene (C₁₆). For example, 2H-inden-2-yl is a C₅cycloalkyl groupwith a substituent (phenyl) fused thereto.

Alkenyl: The term “alkenyl,” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon double bonds. Examples of groups ofalkenyl groups include C₂₋₄alkenyl, C₂₋₇alkenyl, C₂₋₂₀alkenyl.

Examples of (unsubstituted) unsaturated alkenyl groups include, but arenot limited to, ethenyl (vinyl, —CH═CH₂), 1-propenyl (—CH═CH—CH₃),2-propenyl (allyl, —CH—CH═CH₂), isopropenyl (—C(CH₃)═CH₂), butenyl (C₄),pentenyl (C₅), and hexenyl (C₆).

Examples of (unsubstituted) unsaturated cyclic alkenyl groups, which arealso referred to herein as “cycloalkenyl” groups, include, but are notlimited to, cyclopropenyl (C₃), cyclobutenyl (C₄), cyclopentenyl (C₅),and cyclohexenyl (C₆).

Alkynyl: The term “alkynyl,” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon triple bonds. Examples of groups ofalkynyl groups include C₂₋₄alkynyl, C₂₋₇alkynyl, C₂₋₂₀alkynyl.

Examples of (unsubstituted) unsaturated alkynyl groups include, but arenot limited to, ethynyl (ethinyl, —C CH) and 2-propynyl (propargyl,—CH₂—C CH).

Alkylidene: The term “alkylidene,” as used herein, pertains to adivalent monodentate moiety obtained by removing two hydrogen atoms froma carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms(unless otherwise specified), which may be aliphatic or alicyclic, or acombination thereof, and which may be saturated, partially unsaturated,or fully unsaturated. Examples of groups of alkylidene groups includeC₁₋₄alkylidene, C₁₋₇alkylidene, C₁₋₂₀alkylidene.

Examples of alkylidene groups include, but are not limited to,methylidene (═CH₂), ethylidene (═CH—CH₃), vinylidene (═C═CH₂), andisopropylidene (═C(CH₃)₂). An example of a substituted alkylidene isbenzylidene (═CH-Ph).

Alkylidyne: The term “alkylidyne,” as used herein, pertains to atrivalent monodentate moiety obtained by removing three hydrogen atomsfrom a carbon atom of a hydrocarbon compound having from 1 to 20 carbonatoms (unless otherwise specified), which may be aliphatic or alicyclic,or a combination thereof, and which may be saturated, partiallyunsaturated, or fully unsaturated. Examples of groups of alkylidynegroups include C₁₋₄alkylidyne, C₁₋₇alkylidyne, C₁₋₂₀alkylidyne.

Examples of alkylidyne groups include, but are not limited to,methylidyne (CH) and ethylidyne (C—CH₃).

Carbocyclyl: The term “carbocyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a carbocyclic compound, which moiety has from 3 to 20 ring atoms(unless otherwise specified). Preferably, each ring has from 3 to 7 ringatoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms. For example, theterm “C₅₋₆carbocyclyl,” as used herein, pertains to a carbocyclyl grouphaving 5 or 6 ring atoms. Examples of groups of carbocyclyl groupsinclude C₃₋₂₀carbocyclyl, C₃₋₁₀carbocyclyl, C₅₋₁₀carbocyclyl,C₃₋₇carbocyclyl, and C₅₋₇carbocyclyl.

Examples of carbocyclic groups include, but are not limited to, thosedescribed above as cycloalkyl groups; and those described below ascarboaryl groups.

Heterocyclyl: The term “heterocyclyl,” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a heterocyclic compound, which moiety has from 3 to 20 ring atoms(unless otherwise specified), of which from 1 to 10 are ringheteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of whichfrom 1 to 4 are ring heteroatoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₄heterocyclyl,” as usedherein, pertains to a heterocyclyl group having 5 or 6 ring atoms.Examples of groups of heterocyclyl groups include C₃₋₂₀heterocyclyl,C₃₋₇heterocyclyl, C₅₋₇heterocyclyl, and C₅₋₆heterocyclyl.

Examples of (non-aromatic) monocyclic heterocyclyl groups include, butare not limited to, those derived from:

-   N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole)    (C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅),    2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine    (C₆), dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);-   O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅),    oxole (dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆),    dihydropyran (C₆), pyran (C₆), oxepin (C₇);-   S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene)    (C₅), thiane (tetrahydrothiopyran) (C₆), thiepane (C₇); O₂:    dioxolane (C₅), dioxane (C₆), and dioxepane (C₇); O₃: trioxane (C₆);-   N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline    (C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);-   N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅),    tetrahydroisoxazole (C₅), dihydroisoxazole (C₅), morpholine (C₆),    tetrahydrooxazine (C₆), dihydrooxazine (C₆), oxazine (C₆);-   N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);-   N₂O₁: oxadiazine (C₆);-   O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,-   N₁O₁S₁: oxathiazine (C₆).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groupsinclude saccharides, in cyclic form, for example, furanoses (C₅), suchas arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, andpyranoses (C₆), such as allopyranose, altropyranose, glucopyranose,mannopyranose, gulopyranose, idopyranose, galactopyranose, andtalopyranose.

Examples of heterocyclyl groups which are also heteroaryl groups aredescribed below with aryl groups.

Aryl: The term “aryl,” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from an aromatic ring atom of anaromatic compound, which moiety has from 3 to 20 ring atoms (unlessotherwise specified). Preferably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆aryl,” as used herein,pertains to an aryl group having 5 or 6 ring atoms. Examples of groupsof aryl groups include C₃₋₂₀aryl, C₃₋₁₂aryl, C₅₋₁₂aryl, C₅₋₇aryl, andC₅₋₆aryl.

The ring atoms may be all carbon atoms, as in “carboaryl groups” (e.g.,C₅₋₂₀carboaryl).

Examples of carboaryl groups include, but are not limited to, thosederived from benzene (i.e., phenyl) (C₆), naphthalene (C₁₀), azulene(C₁₀), anthracene (C₁₄), phenanthrene (C₁₄), naphthacene (C₁₈), andpyrene (C₁₆).

Examples of aryl groups which comprise fused rings, at least one ofwhich is an aromatic ring, include, but are not limited to, groupsderived from indene (C₉), isoindene (C₉), and fluorene (C₁₃).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroaryl groups” (e.g., C₅₋₂₀heteroaryl). Examples of monocyclicheteroaryl groups include, but are not limited to, those derived from:

-   N₁: pyrrole (azole) (C₅), pyridine (azine) (C₆);-   O₁: furan (oxole) (C₅);-   S₁: thiophene (thiole) (C₅);-   N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆);-   N₂O₁: oxadiazole (furazan) (C₅);-   N₃O₁: oxatriazole (C₅);-   N₁S₁: thiazole (C₅), isothiazole (C₅);-   N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅),    pyridazine (1,2-diazine) (C₆), pyrimidine (1,3-diazine) (C₆) (e.g.,    cytosine, thymine, uracil), pyrazine (1,4-diazine) (C₆);-   N₃: triazole (C₅), triazine (C₆); and,-   N₄: tetrazole (C₅).

Examples of heterocyclic groups (some of which are also heteroarylgroups) which comprise fused rings, include, but are not limited to:

C₉heterocyclic groups (with 2 fused rings) derived from benzofuran (O₁),isobenzofuran (O₁), indole (N₁), isoindole (N₁), indolizine (N₁),indoline (N₁), isoindoline (N₁), purine (N₄) (e.g., adenine, guanine),benzimidazole (N₂), indazole (N₂), benzoxazole (N₁O₁), benzisoxazole(N₁O₁), benzodioxole (O₂), benzofurazan (N₂O₁), benzotriazole (N₃),benzothiofuran (S₁), benzothiazole (N₁S₁), benzothiadiazole (N₂S);

-   -   C₁₀heterocyclic groups (with 2 fused rings) derived from        chromene (01), isochromene (O₁), chroman (O₁), isochroman (O₁),        benzodioxan (O₂), quinoline (N₁), isoquinoline (N₁), quinolizine        (N₁), benzoxazine (N₁O₁), benzodiazine (N₂), pyridopyridine        (N₂), quinoxaline (N₂), quinazoline (N₂), cinnoline (N₂),        phthalazine (N₂), naphthyridine (N₂), pteridine (N₄);    -   C₁₃heterocyclic groups (with 3 fused rings) derived from        carbazole (N₁), dibenzofuran (O₁), dibenzothiophene (S₁),        carboline (N₂), perimidine (N₂), pyridoindole (N₂); and,    -   C₁₄heterocyclic groups (with 3 fused rings) derived from        acridine (N₁), xanthene (O₁), thioxanthene (S₁), oxanthrene        (O₂), phenoxathiin (O₁S₁), phenazine (N₂), phenoxazine (N₁O₁),        phenothiazine (N₁S₁), thianthrene (S₂), phenanthridine (N₂),        phenanthroline (N₂), phenazine (N₂).

Heterocyclic groups (including heteroaryl groups) which have a nitrogenring atom in the form of an—NH— group may be N-substituted, that is,as—NR—. For example, pyrrole may be N-methyl substituted, to giveN-methypyrrole. Examples of N-substituents include, but are not limitedto C₁₋₇alkyl, C₃₋₂₀heterocyclyl, C₅₋₂₀aryl, and acyl groups.

Heterocyclic groups (including heteroaryl groups) which have a nitrogenring atom in the form of an—N═ group may be substituted in the form ofan N-oxide, that is, as—N(O)═(also denoted—N⁺(O⁻)═). For example,quinoline may be substituted to give quinoline N-oxide; pyridine to givepyridine N-oxide; benzofurazan to give benzofurazan N-oxide (also knownas benzofuroxan).

Cyclic groups may additionally bear one or more oxo (═O) groups on ringcarbon atoms. Monocyclic examples of such groups include, but are notlimited to, those derived from:

-   C₅: cyclopentanone, cyclopentenone, cyclopentadienone;-   C₆: cyclohexanone, cyclohexenone, cyclohexadienone;-   O₁: furanone (C₅), pyrone (C₆);-   N₁: pyrrolidone (pyrrolidinone) (C₅), piperidinone (piperidone)    (C₆), piperidinedione (C₆);-   N₂: imidazolidone (imidazolidinone) (C₅), pyrazolone (pyrazolinone)    (C₅), piperazinone-   (C₆), piperazinedione (C₆), pyridazinone (C₆), pyrimidinone (C₆)    (e.g., cytosine), pyrimidinedione (C₆) (e.g., thymine, uracil),    barbituric acid (C₆);-   N₁S₁: thiazolone (C₅), isothiazolone (C₅);-   N₁O₁: oxazolinone (C₅).

Polycyclic examples of such groups include, but are not limited to,those derived from:

-   C₉: indenedione;-   C₁₀: tetralone, decalone;-   C₁₄: anthrone, phenanthrone;-   N₁: oxindole (C₉);-   O₁: benzopyrone (e.g., coumarin, isocoumarin, chromone) (C₁₀);-   N₁O₁: benzoxazolinone (C₉), benzoxazolinone (C₁₀);-   N₂: quinazolinedione (C₁₀);-   N₄: purinone (C₉) (e.g., guanine).

Still more examples of cyclic groups which bear one or more oxo (═O)groups on ring carbon atoms include, but are not limited to, thosederived from:

-   -   cyclic anhydrides (—C(═O)—O—C(═O)— in a ring), including but not        limited to maleic anhydride (C₅), succinic anhydride (C₅), and        glutaric anhydride (C₆);    -   cyclic carbonates (—O—C(═O)—O— in a ring), such as ethylene        carbonate (C₅) and 1,2-propylene carbonate (C₅);    -   imides (—C(═O)—NR—C(═O)— in a ring), including but not limited        to, succinimide (C₅), maleimide (C₅), phthalimide, and        glutarimide (C₆);    -   lactones (cyclic esters, —O—C(═O)— in a ring), including, but        not limited to, β-propiolactone, γ-butyrolactone,        δ-valerolactone (2-piperidone), and ε-caprolactone;    -   lactams (cyclic amides, —NR—C(═O)— in a ring), including, but        not limited to, β-propiolactam (C₄), γ-butyrolactam        (2-pyrrolidone) (C₅), δ-valerolactam (C₆), and ε-caprolactam        (C₇);    -   cyclic carbamates (—O—C(═O)—NR— in a ring), such as        2-oxazolidone (C₅);    -   cyclic ureas (—NR—C(═O)—NR— in a ring), such as 2-imidazolidone        (C₅) and pyrimidine-2,4-dione (e.g., thymine, uracil) (C₆).

The above alkyl, alkylidene, alkylidyne, heterocyclyl, and aryl groups,whether alone or part of another substituent, may themselves optionallybe substituted with one or more groups selected from themselves and theadditional substituents listed below.

-   Hydrogen:—H. Note that if the substituent at a particular position    is hydrogen, it may be convenient to refer to the compound as being    “unsubstituted” at that position.-   Halo:—F, —Cl, —Br, and—I.-   Hydroxy:—OH.-   Ether:—OR, wherein R is an ether substituent, for example, a    C₁₋₇alkyl group (also referred to as a C₁₋₇alkoxy group, discussed    below), a C₃₋₂₀heterocyclyl group (also referred to as a    C₃₋₂₀heterocyclyloxy group), or a C₅₋₂₀aryl group (also referred to    as a C₅₋₂₀aryloxy group), preferably a C₁₋₇alkyl group.-   C₁₋₇alkoxy:—OR, wherein R is a C₁₋₇alkyl group. Examples of    C₁₋₇alkoxy groups include, but are not limited to, —OMe (methoxy),    —OEt (ethoxy), —O(nPr) (n-propoxy), —O(iPr) (isopropoxy), —O(nBu)    (n-butoxy), —O(sBu) (sec-butoxy), —O(iBu) (isobutoxy), and—O(tBu)    (tert-butoxy).-   Acetal:—CH(OR¹)(OR²), wherein R¹ and R² are independently acetal    substituents, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl    group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group, or, in    the case of a “cyclic” acetal group, R¹ and R², taken together with    the two oxygen atoms to which they are attached, and the carbon    atoms to which they are attached, form a heterocyclic ring having    from 4 to 8 ring atoms. Examples of acetal groups include, but are    not limited to, —CH(OMe)₂, —CH(OEt)₂, and—CH(OMe)(OEt).-   Hemiacetal:—CH(OH)(OR¹), wherein R¹ is a hemiacetal substituent, for    example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a    C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of    hemiacetal groups include, but are not limited to, —CH(OH)(OMe) and    —CH(OH)(OEt).-   Ketal:—CR(OR¹)(OR²), where R¹ and R² are as defined for acetals, and    R is a ketal substituent other than hydrogen, for example, a    C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,    preferably a C₁₋₇alkyl group. Examples ketal groups include, but are    not limited to, —C(Me)(OMe)₂, —C(Me)(OEt)₂, —C(Me)(OMe)(OEt),    —C(Et)(OMe)₂, —C(Et)(OEt)₂, and—C(Et)(OMe)(OEt).-   Hemiketal:—CR(OH)(OR¹), where R¹ is as defined for hemiacetals, and    R is a hemiketal substituent other than hydrogen, for example, a    C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,    preferably a C₁₋₇alkyl group. Examples of hemiacetal groups include,    but are not limited to, —C(Me)(OH)(OMe), —C(Et)(OH)(OMe),    —C(Me)(OH)(OEt), and —C(Et)(OH)(OEt).-   Oxo (keto, -one): ═O.-   Thione (thioketone): ═S.-   Imino (imine): ═NR, wherein R is an imino substituent, for example,    hydrogen, C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl    group, preferably hydrogen or a C₁₋₇alkyl group. Examples of ester    groups include, but are not limited to, ═NH, ═NMe, ═NEt, and ═NPh.-   Formyl (carbaldehyde, carboxaldehyde):—C(═O)H.-   Acyl (keto):—C(═O)R, wherein R is an acyl substituent, for example,    a C₁₋₇alkyl group (also referred to as C₁₋₇alkylacyl or    C₁₋₇alkanoyl), a C₃₋₂₀heterocyclyl group (also referred to as    C₃₋₂₀heterocyclylacyl), or a C₅₋₂₀aryl group (also referred to as    C₅₋₂₀arylacyl), preferably a C₁₋₇alkyl group. Examples of acyl    groups include, but are not limited to, —C(═O)CH₃ (acetyl),    —C(═O)CH₂CH₃ (propionyl), —C(═O)C(CH₃)₃ (t-butyryl), and—C(═O)Ph    (benzoyl, phenone).-   Acylhalide (haloformyl, halocarbonyl):—C(═O)X, wherein X is—F, —Cl,    —Br, or —I, preferably —Cl, —Br, or —I.-   Carboxy (carboxylic acid):—C(═O)OH.-   Thiocarboxy (thiocarboxylic acid):—C(═S)SH.-   Thiolocarboxy (thiolocarboxylic acid):—C(═O)SH.-   Thionocarboxy (thionocarboxylic acid):—C(═S)OH.-   Imidic acid:—C(═NH)OH.-   Hydroxamic acid:—C(═NOH)OH.-   Ester (carboxylate, carboxylic acid ester, oxycarbonyl):—C(═O)OR,    wherein R is an ester substituent, for example, a C₁₋₇alkyl group, a    C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a    C₁₋₇alkyl group. Examples of ester groups include, but are not    limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and—C(═O)OPh.-   Acyloxy (reverse ester):—OC(═O)R, wherein R is an acyloxy    substituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl    group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples    of acyloxy groups include, but are not limited to, —OC(═O)CH₃    (acetoxy), —OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph,    and—OC(═O)CH₂Ph.-   Oxycarboyloxy:—OC(═O)OR, wherein R is an ester substituent, for    example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a    C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of ester    groups include, but are not limited to, —OC(═O)OCH₃, —OC(═O)OCH₂CH₃,    —OC(═O)OC(CH₃)₃, and—OC(═O)OPh.-   Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide):—C(═O)NR¹R²,    wherein R¹ and R² are independently amino substituents, as defined    for amino groups. Examples of amido groups include, but are not    limited to, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃,    and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R²,    together with the nitrogen atom to which they are attached, form a    heterocyclic structure as in, for example, piperidinocarbonyl,    morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.-   Acylamido (acylamino):—NR¹C(═O)R², wherein R¹ is an amide    substituent, for example, hydrogen, a C₁₋₇alkyl group, a    C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably hydrogen    or a C₁₋₇alkyl group, and R² is an acyl substituent, for example, a    C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,    preferably hydrogen or a C₁₋₇alkyl group. Examples of acylamide    groups include, but are not limited to, —NHC(═O)CH₃, —NHC(═O)CH₂CH₃,    and—NHC(═O)Ph. R¹ and R² may together form a cyclic structure, as    in, for example, succinimidyl, maleimidyl, and phthalimidyl:

-   Aminocarbonyloxy:—OC(═O)NR¹R², wherein R¹ and R² are independently    amino substituents, as defined for amino groups. Examples of    aminocarbonyloxy groups include, but are not limited to, —OC(═O)NH₂,    —OC(═O)NHMe, —OC(═O)NMe₂, and—OC(═O)NEt₂.-   Thioamido (thiocarbamyl):—C(═S)NR¹R², wherein R¹ and R² are    independently amino substituents, as defined for amino groups.    Examples of amido groups include, but are not limited to, —C(═S)NH₂,    —C(═S)NHCH₃, —C(═S)N(CH₃)₂, and—C(═S)NHCH₂CH₃.-   Ureido:—N(R¹)CONR²R³ wherein R² and R³ are independently amino    substituents, as defined for amino groups, and R¹ is a ureido    substituent, for example, hydrogen, a C₁₋₇alkyl group, a    C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably hydrogen    or a C₁₋₇alkyl group. Examples of ureido groups include, but are not    limited to, —NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂,    —NMeCONH₂, —NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, and—NMeCONEt₂.-   Guanidino:—NH—C(═NH)NH₂.

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms andone carbon atom,

-   Amino:—NR¹R², wherein R¹ and R² are independently amino    substituents, for example, hydrogen, a C₁₋₇alkyl group (also    referred to as C₁₋₇alkylamino or di-C₁₋₇alkylamino), a    C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably H or a    C₁₋₇alkyl group, or, in the case of a “cyclic” amino group, R¹ and    R², taken together with the nitrogen atom to which they are    attached, form a heterocyclic ring having from 4 to 8 ring atoms.    Amino groups may be primary (—NH₂), secondary (—NHR¹), or tertiary    (—NHR¹R²), and in cationic form, may be quaternary (—⁺NR¹R²R³).    Examples of amino groups include, but are not limited to, —NH₂,    —NHCH₃, —NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and—NHPh. Examples of    cyclic amino groups include, but are not limited to, aziridino,    azetidino, pyrrolidino, piperidino, piperazino, morpholino, and    thiomorpholino.-   Imino: ═NR, wherein R is an imino substituent, for example, for    example, hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or    a C₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group. Examples of    imino groups include, but are not limited to, ═NH, ═NMe, and ═NEt.-   Amidine (amidino):—C(═NR)NR₂, wherein each R is an amidine    substituent, for example, hydrogen, a C₁₋₇alkyl group, a    C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably H or a    C₁₋₇alkyl group. Examples of amidine groups include, but are not    limited to, —C(═NH)NH₂, —C(═NH)NMe₂, and—C(═NMe)NMe₂.-   Nitro:—NO₂.-   Cyano (nitrile, carbonitrile):—CN.-   Isocyano:—NC.-   Cyanato:—OCN.-   Isocyanato:—NCO.-   Isothiocyano (isothiocyanato):—NCS.-   Sulfhydryl (thiol, mercapto):—SH.-   Thioether (sulfide):—SR, wherein R is a thioether substituent, for    example, a C₁₋₇alkyl group (also referred to as a C₁₋₇alkylthio    group), a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably    a C₁₋₇alkyl group. Examples of C₁₋₇alkylthio groups include, but are    not limited to, —SCH₃ and —SCH₂CH₃.-   Disulfide:—SS—R, wherein R is a disulfide substituent, for example,    a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,    preferably a C₁₋₇alkyl group (also referred to herein as C₁₋₇alkyl    disulfide). Examples of C₁₋₇alkyl disulfide groups include, but are    not limited to, —SSCH₃ and —SSCH₂CH₃.-   Sulfine (sulfinyl, sulfoxide):—S(═O)R, wherein R is a sulfine    substituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl    group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples    of sulfine groups include, but are not limited to, —S(═O)CH₃ and    —S(═O)CH₂CH₃.-   Sulfone (sulfonyl):—S(═O)₂R, wherein R is a sulfone substituent, for    example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a    C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group, including, for    example, a fluorinated or perfluorinated C₁₋₇alkyl group. Examples    of sulfone groups include, but are not limited to, —S(═O)₂CH₃    (methanesulfonyl, mesyl), —S(═O)₂CF₃ (triflyl), —S(═O)₂CH₂CH₃    (esyl), —S(═O)₂C₄F₉ (nonaflyl), —S(═O)₂CH₂CF₃ (tresyl),    —S(═O)₂CH₂CH₂NH₂ (tauryl), —S(═O)₂Ph (phenylsulfonyl, besyl),    4-methylphenylsulfonyl (tosyl), 4-chlorophenylsulfonyl (closyl),    4-bromophenylsulfonyl (brosyl), 4-nitrophenyl (nosyl),    2-naphthalenesulfonate (napsyl), and    5-dimethylamino-naphthalen-1-ylsulfonate (dansyl).-   Sulfinic acid (sulfino):—S(═O)OH, —SO₂H.-   Sulfonic acid (sulfo):—S(═O)₂OH, —SO₃H.-   Sulfinate (sulfinic acid ester):—S(═O)OR; wherein R is a sulfinate    substituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl    group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples    of sulfinate groups include, but are not limited to, —S(═O)OCH₃    (methoxysulfinyl; methyl sulfinate) and —S(═O)OCH₂CH₃    (ethoxysulfinyl; ethyl sulfinate).-   Sulfonate (sulfonic acid ester):—S(═O)₂OR, wherein R is a sulfonate    substituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl    group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples    of sulfonate groups include, but are not limited to, —S(═O)₂OCH₃    (methoxysulfonyl; methyl sulfonate) and—S(═O)₂OCH₂CH₃    (ethoxysulfonyl; ethyl sulfonate).-   Sulfinyloxy:—OS(═O)R, wherein R is a sulfinyloxy substituent, for    example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a    C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of    sulfinyloxy groups include, but are not limited to, —OS(═O)CH₃ and    —OS(═O)CH₂CH₃.-   Sulfonyloxy:—OS(═O)₂R, wherein R is a sulfonyloxy substituent, for    example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a    C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of    sulfonyloxy groups include, but are not limited to, —OS(═O)₂CH₃    (mesylate) and —OS(═O)₂CH₂CH₃ (esylate).-   Sulfate:—OS(═O)₂OR; wherein R is a sulfate substituent, for example,    a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,    preferably a C₁₋₇alkyl group. Examples of sulfate groups include,    but are not limited to, —OS(═O)₂OCH₃ and —SO(═O)₂OCH₂CH₃.-   Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide):—S(═O)NR¹R²,    wherein R¹ and R² are independently amino substituents, as defined    for amino groups. Examples of sulfamyl groups include, but are not    limited to, —S(═O)NH₂, —S(═O)NH(CH₃), —S(═O)N(CH₃)₂,    —S(═O)NH(CH₂CH₃), —S(═O)N(CH₂CH₃)₂, and—S(═O)NHPh.-   Sulfonamido (sulfinamoyl; sulfonic acid amide;    sulfonamide):—S(═O)₂NR¹R², wherein R¹ and R² are independently amino    substituents, as defined for amino groups. Examples of sulfonamido    groups include, but are not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃),    —S(═O)₂N(CH₃)₂, —S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂,    and—S(═O)₂NHPh.-   Sulfamino:—NR¹S(═O)₂OH, wherein R¹ is an amino substituent, as    defined for amino groups. Examples of sulfamino groups include, but    are not limited to, —NHS(═O)₂OH and —N(CH₃)S(═O)₂OH.-   Sulfonamino:—NR¹S(═O)₂R, wherein R¹ is an amino substituent, as    defined for amino groups, and R is a sulfonamino substituent, for    example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a    C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of    sulfonamino groups include, but are not limited to, —NHS(═O)₂CH₃ and    —N(CH₃)S(═O)₂C₆H₅.-   Sulfinamino:—NR¹S(═O)R, wherein R¹ is an amino substituent, as    defined for amino groups, and R is a sulfinamino substituent, for    example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a    C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of    sulfinamino groups include, but are not limited to, —NHS(═O)CH₃ and    —N(CH₃)S(═O)C₆H₅.

In many cases, substituents may themselves be substituted. For example,a C₁₋₇alkyl group may be substituted with, for example, hydroxy (alsoreferred to as a C₁₋₇hydroxyalkyl group), C₁₋₇alkoxy (also referred toas a C₁₋₇alkoxyalkyl group), amino (also referred to as a C₁₋₇aminoalkylgroup), halo (also referred to as a C₁₋₇haloalkyl group), carboxy (alsoreferred to as a C₁₋₇carboxyalkyl group), and C₅₋₂₀aryl (also referredto as a C₅₋₂₀aryl-C₁₋₇alkyl group).

Similarly, a C₅₋₂₀aryl group may be substituted with, for example,hydroxy (also referred to as a C₅₋₂₀hydroxyaryl group), halo (alsoreferred to as a C₅₋₂₀haloaryl group), amino (also referred to as aC₅₋₂₀aminoaryl group, e.g., as in aniline), C₁₋₇alkyl (also referred toas a C₁₋₇alkyl-C₅₋₂₀aryl group, e.g., as in toluene), and C₁₋₇alkoxy(also referred to as a C₁₋₇alkoxy-C₅₋₂₀aryl group, e.g., as in anisole).

These and other specific examples of such substituted-substituents aredescribed below.

-   Hydroxy-C₁₋₇alkyl: The term “hydroxy-C₁₋₇alkyl,” as used herein,    pertains to a C₁₋₇alkyl group in which at least one hydrogen atom    (e.g., 1, 2, 3) has been replaced with a hydroxy group. Examples of    such groups include, but are not limited to, —CH₂OH, —CH₂CH₂OH, and    —CH(OH)CH₂OH.-   Halo-C₁₋₇alkyl group: The term “halo-C₁₋₇alkyl,” as used herein,    pertains to a C₁₋₇alkyl group in which at least one hydrogen atom    (e.g., 1, 2, 3) has been replaced with a halogen atom (e.g., F, Cl,    Br, I). If more than one hydrogen atom has been replaced with a    halogen atom, the halogen atoms may independently be the same or    different. Every hydrogen atom may be replaced with a halogen atom,    in which case the group may conveniently be referred to as a    C₁₋₇perhaloalkyl group.” Examples of such groups include, but are    not limited to, —CF₃, —CHF₂, —CH₂F, —CCl₃, —CBr₃, —CH₂CH₂F,    —CH₂CHF₂, and —CH₂CF₃.-   Amino-C₁₋₇alkyl: The term “amino-C₁₋₇alkyl,” as used herein,    pertains to a C₁₋₇alkyl group in which at least one hydrogen atom    (e.g., 1, 2, 3) has been replaced with an amino group. Examples of    such groups include, but are not limited to, —CH₂NH₂, —CH₂CH₂NH₂,    and —CH₂CH₂N(CH₃)₂.-   Carboxy-C₁₋₇alkyl: The term “carboxy-C₁₋₇alkyl,” as used herein,    pertains to a C₁₋₇alkyl group in which at least one hydrogen atom    (e.g., 1, 2, 3) has been replaced with a carboxy group. Examples of    such groups include, but are not limited to, —CH₂COOH and    —CH₂CH₂COOH.-   C₁₋₇alkoxy-C₁₋₇alkyl: The term “C₁₋₇alkoxy-C₁₋₇alkyl,” as used    herein, pertains to a C₁₋₇alkyl group in which at least one hydrogen    atom (e.g., 1, 2, 3) has been replaced with a C₁₋₇alkoxy group.    Examples of such groups include, but are not limited to, —CH₂OCH₃,    —CH₂CH₂OCH₃, and, —CH₂CH₂OCH₂CH₃-   C₅₋₂₀aryl-C₁₋₇alkyl: The term “C₅₋₂₀aryl-C₁₋₇alkyl,” as used herein,    pertains to a C₁₋₇alkyl group in which at least one hydrogen atom    (e.g., 1, 2, 3) has been replaced with a C₅₋₂₀aryl group. Examples    of such groups include, but are not limited to, benzyl    (phenylmethyl, PhCH₂—), benzhydryl (Ph₂CH—), trityl    (triphenylmethyl, Ph₃C—), phenethyl (phenylethyl, Ph-CH₂CH₂—),    styryl (Ph-CH═CH—), cinnamyl (Ph-CH═CH—CH₂—).-   Hydroxy-C₅₋₂₀aryl: The term “hydroxy-C₅₋₂₀aryl,” as used herein,    pertains to a C₅₋₂₀aryl group in which at least one hydrogen atom    (e.g., 1, 2, 3) has been substituted with an hydroxy group. Examples    of such groups include, but are not limited to, those derived from:    phenol, naphthol, pyrocatechol, resorcinol, hydroquinone,    pyrogallol, phloroglucinol.-   Halo-C₅₋₂₀aryl: The term “halo-C₅₋₂₀aryl,” as used herein, pertains    to a C₅₋₂₀aryl group in which at least one hydrogen atom (e.g., 1,    2, 3) has been substituted with a halo (e.g., F, Cl, Br, I) group.    Examples of such groups include, but are not limited to, halophenyl    (e.g., fluorophenyl, chlorophenyl, bromophenyl, or iodophenyl,    whether ortho-, meta-, or para-substituted), dihalophenyl,    trihalophenyl, tetrahalophenyl, and pentahalophenyl.-   C₁₋₇alkyl-C₅₋₂₀aryl: The term “C₁₋₇alkyl-C₅₋₂₀aryl,” as used herein,    pertains to a C₅₋₂₀aryl group in which at least one hydrogen atom    (e.g., 1, 2, 3) has been substituted with a C₁₋₇alkyl group.    Examples of such groups include, but are not limited to, tolyl (from    toluene), xylyl (from xylene), mesityl (from mesitylene), and    cumenyl (or cumyl, from cumene), and duryl (from durene).-   Hydroxy-C₁₋₇alkoxy:—OR, wherein R is a hydroxy-C₁₋₇alkyl group.    Examples of hydroxy-C₁₋₇alkoxy groups include, but are not limited    to, —OCH₂OH, —OCH₂CH₂OH, and —OCH₂CH₂CH₂OH.-   Halo-C₁₋₇alkoxy:—OR, wherein R is a halo-C₁₋₇alkyl group. Examples    of halo-C₁₋₇alkoxy groups include, but are not limited to, —OCF₃,    —OCHF₂, —OCH₂F, —OCCl₃, —OCBr₃, —OCH₂CH₂F, —OCH₂CHF₂, and —OCH₂CF₃.-   Carboxy-C₁₋₇alkoxy:—OR, wherein R is a carboxy-C₁₋₇alkyl group.    Examples of carboxy-C₁₋₇alkoxy groups include, but are not limited    to, —OCH₂COOH, —OCH₂CH₂COOH, and —OCH₂CH₂CH₂COOH.-   C₁₋₇alkoxy-C₁₋₇alkoxy:—OR, wherein R is a C₁₋₇alkoxy-C₁₋₇alkyl    group. Examples of C₁₋₇alkoxy-C₁₋₇alkoxy groups include, but are not    limited to, —OCH₂OCH₃, —OCH₂CH₂OCH₃, And —OCH₂CH₂OCH₂CH₃.-   C₅₋₂₀aryl-C₁₋₇alkoxy:—OR, wherein R is a C₅₋₂₀aryl-C₁₋₇alkyl group.    Examples of such groups include, but are not limited to, benzyloxy,    benzhydryloxy, trityloxy, phenethoxy, styryloxy, and cimmamyloxy.-   C₁₋₇alkyl-C₅₋₂₀aryloxy:—OR, wherein R is a C₁₋₇alkyl-C₅₋₂₀aryl    group. Examples of such groups include, but are not limited to,    tolyloxy, xylyloxy, mesityloxy, cumenyloxy, and duryloxy.-   Amino-C₁₋₇alkyl-amino: The term “amino-C₁₋₇alkyl-amino,” as used    herein, pertains to an amino group, —NR¹R², in which one of the    substituents, R¹ or R², is itself a amino-C₁₋₇alkyl group    (—C₁₋₇alkyl-NR³R⁴). The amino-C₁₋₇alkylamino group may be    represented, for example, by the formula —NR¹—C₁₋₇alkyl-NR³R⁴.    Examples of such groups include, but are not limited to, groups of    the formula —NR¹(CH₂)_(n)NR¹R², where n is 1 to 6 (for example,    —NHCH₂NH₂, —NH(CH₂)₂NH₂, —N H(CH₂)₃NH₂, —NH(CH₂)₄NH₂, —NH(CH₂)₅NH₂,    —NH(CH₂)₆NH₂), —NHCH₂NH(Me), —NH(CH₂)₂NH(Me), —NH(CH₂)₃NH(Me),    —NH(CH₂)₄NH(Me), —NH(CH₂)₅NH(Me), —NH(CH₂)₆NH(Me), —NHCH₂NH(Et),    —NH(CH₂)₂NH(Et), —NH(CH₂)₃NH(Et), —NH(CH₂)₄NH(Et), —NH(CH₂)₅NH(Et),    and —NH(CH₂)₆NH(Et).    Bidentate Substituents

The term “bidentate substituents,” as used herein, pertains tosubstituents which have two points of covalent attachment, and which actas a linking group between two other moieties.

In some cases (A), a bidentate substituent is covalently bound to asingle atom. In some cases (B), a bidentate substituent is covalentlybound to two different atoms, and so serves as a linking grouptherebetween.

-   -   (B) A₁-bidentate group-A₂

Within (B), in some cases (C), a bidentate substituent is covalentlybound to two different atoms, which themselves are not otherwisecovalently linked (directly, or via intermediate groups). In some cases(D), a bidentate substituent is covalently bound to two different atoms,which themselves are already covalently linked (directly, or viaintermediate groups); in such cases, a cyclic structure results. In somecases, the bidentate group is covalently bound to vicinal atoms, thatis, adjacent atoms, in the parent group.

-   -   (C) A₁-bidentate group-A₂

In some cases (A and D), the bidentate group, together with the atom(s)to which it is attached (and any intervening atoms, if present) form anadditional cyclic structure. In this way, the bidentate substituent maygive rise to a cyclic or polycyclic (e.g., fused, bridged, spiro)structure, which may be aromatic.

Examples of bidentate groups include, but are not limited to,C₁₋₇alkylene groups, C₃₋₂₀heterocyclylene groups, and C₅₋₂₀arylenegroups, and substituted forms thereof.

Alkylene

Alkylene: The term “alkylene,” as used herein, pertains to a bidentatemoiety obtained by removing two hydrogen atoms, either both from thesame carbon atom, or one from each of two different carbon atoms, of ahydrocarbon compound having from 1 to 20 carbon atoms (unless otherwisespecified), which may be aliphatic or alicyclic, and which may besaturated, partially unsaturated, or fully unsaturated. Thus, the term“alkylene” includes the sub-classes alkenylene, alkynylene,cycloalkylene, etc., discussed below.

In this context, the prefixes (e.g., C₁₋₄, C₁₋₇, C₁₋₂₀, C₂₋₇, C₃₋₇,etc.) denote the number of carbon atoms, or range of number of carbonatoms. For example, the term “C₁₋₄alkylene,” as used herein, pertains toan alkylene group having from 1 to 4 carbon atoms. Examples of groups ofalkylene groups include C₁₋₄alkylene (“lower alkylene”), C₁₋₇alkylene,and C₁₋₂₀alkylene.

Examples of linear saturated C₁₋₇alkylene groups include, but are notlimited to, —(CH₂)_(n)— where n is an integer from 1 to 7, for example,—CH₂— (methylene), —CH₂CH₂— (ethylene), —CH₂CH₂CH₂— (propylene), and 3CH₂CH₂CH₂CH₂— (butylene).

Examples of branched saturated C₂₋₇alkylene groups include, but are notlimited to, —CH(CH₃)—, —CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—,—CH(CH₃)CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —CH(CH₂CH₃) —,—CH(CH₂CH₃)CH₂—, and —CH₂CH(CH₂CH₃)CH₂—.

Examples of linear partially unsaturated C₂₋₇alkylene groups include,but is not limited to; —CH═CH — (vinylene), —CH═CH—CH₂—, —CH═CH—CH₂—CH₂-, 13 CH═CH —CH₂—CH₂—CH₂—, —CH═CH—CH═CH—, —CH═CH —CH═CH —CH₂—,—CH═CH —CH═CH —CH₂—CH₂—, —CH═CH—CH₂—CH═CH—, and —CH═CH—CH₂—CH₂—CH═CH—.

Examples of branched partially unsaturated C₂₋₇alkylene groups include,but is not limited to, —C(CH₃)═CH—, —C(CH₃)═CH —CH₂—, and —CH═CH—CH(CH₃)—.

Examples of alicyclic saturated C₃₋₇alkylene groups include, but are notlimited to, cyclopentylene (e.g., cyclopent-1,3-ylene), andcyclohexylene (e.g., cyclohex-1,4-ylene).

Examples of alicyclic partially unsaturated C₃₋₇alkylene groups include,but are not limited to, cyclopentenylene (e.g.,4-cyclopenten-1,3-ylene), cyclohexenylene (e.g., 2-cyclohexen-1,4-ylene;3-cyclohexen-1,2-ylene; 2,5-cyclohexadien-1,4-ylene).

Arylene

-   Arylene: The term “arylene,” as used herein, pertains to a bidentate    moiety obtained by removing two hydrogen atoms, one from each of two    different aromatic ring atoms of an aromatic compound, which moiety    has from 3 to 20 ring atoms (unless otherwise specified).    Preferably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g., C₃₋₂₀, C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆arylene,” as usedherein, pertains to an arylene group having 5 or 6 ring atoms. Examplesof groups of arylene groups include C₃₋₂₀arylene, C₃₋₁₂arylene,C₅₋₁₂arylene, C₅₋₇arylene, and C₅₋₆arylene.

The ring atoms may be all carbon atoms, as in “carboarylene groups”(e.g., C₅₋₂₀carboarylene).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroarylene groups” (e.g., C₅₋₂₀heteroarylene).

Examples of C₅₋₂₀arylene groups which do not have ring heteroatoms(i.e., C₅₋₂₀carboarylene groups) include, but are not limited to, thosederived from the compounds discussed above in regard to carboarylgroups.

Examples of C₅₋₂₀heteroarylene groups include, but are not limited to,those derived from the compounds discussed above in regard to heteroarylgroups.

Includes Other Forms

Unless otherwise specified, included in the above are the well knownionic, salt, solvate, and protected forms of these substituents. Forexample, a reference to carboxylic acid (—COOH) also includes theanionic (carboxylate) form (—COO⁻), a salt or solvate thereof, as wellas conventional protected forms. Similarly, a reference to an aminogroup includes the protonated form (—N⁺HR¹R²), a salt or solvate of theamino group, for example, a hydrochloride salt, as well as conventionalprotected forms of an amino group. Similarly, a reference to a hydroxylgroup also includes the anionic form (—O⁻), a salt or solvate thereof,as well as conventional protected forms.

Isomers, Salts, Solvates, Protected Forms, and Prodrugs

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, atropic,stereoisomeric, tautomeric, conformational, or anomeric forms, includingbut not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, andr-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d-and l-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn-and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axialand equatorial forms; boat-, chair-, twist-, envelope-, andhalfchair-forms; and combinations thereof, hereinafter collectivelyreferred to as “isomers” (or “isomeric forms”).

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁₋₇alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including (wholly or partially)racemic and other mixtures thereof. Methods for the preparation (e.g.,asymmetric synthesis) and separation (e.g., fractional crystallisationand chromatographic means) of such isomeric forms are either known inthe art or are readily obtained by adapting the methods taught herein,or known methods, in a known manner.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms of thereof, forexample, as discussed below.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be—COO⁻), then a salt may be formed witha suitable cation. Examples of suitable inorganic cations include, butare not limited to, alkali metal ions such as Na⁺and K⁺, alkaline earthcations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³. Examplesof suitable organic cations include, but are not limited to, ammoniumion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺, NH₂R₂ ⁺,NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammonium ions arethose derived from: ethylamine, diethylamine, dicyclohexylamine,triethylamine, butylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline,meglumine, and tromethamine, as well as amino acids, such as lysine andarginine. An example of a common quaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be—NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the active compound. The term “solvate” is usedherein in the conventional sense to refer to a complex of solute (e.g.,active compound, salt of active compound) and solvent. If the solvent iswater, the solvate may be conveniently referred to as a hydrate, forexample, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in a chemically protected form. The term “chemicallyprotected form” is used herein in the conventional chemical sense andpertains to a compound in which one or more reactive functional groupsare protected from undesirable chemical reactions under specifiedconditions (e.g., pH, temperature, radiation, solvent, and the like). Inpractice, well known chemical methods are employed to reversibly renderunreactive a functional group, which otherwise would be reactive, underspecified conditions. In a chemically protected form, one or morereactive functional groups are in the form of a protected or protectinggroup (also known as a masked or masking group or a blocked or blockinggroup). By protecting a reactive functional group, reactions involvingother unprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley andSons, 1999).

A wide variety of such “protecting,” “blocking,” or “masking” methodsare widely used and well known in organic synthesis. For example, acompound which has two nonequivalent reactive functional groups, both ofwhich would be reactive under specified conditions, may be derivatizedto render one of the functional groups “protected,” and thereforeunreactive, under the specified conditions; so protected, the compoundmay be used as a reactant which has effectively only one reactivefunctional group. After the desired reaction (involving the otherfunctional group) is complete, the protected group may be “deprotected”to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid.

For example, an amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), as a2(-phenylsulphonyl)ethyloxy amide (—NH-Psec); or, in suitable cases(e.g., cyclic amines), as a nitroxide radical (>N—O.).

For example, a carboxylic acid group may be protected as an ester forexample, as: an C₁₋₇alkyl ester (e.g., a methyl ester; a t-butyl ester);a C₁₋₇haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); atriC₁₋₇alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇alkyl ester (e.g.,a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as amethyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in the form of a prodrug. The term “prodrug,” as usedherein, pertains to a compound which, when metabolised (e.g., in vivo),yields the desired active compound. Typically, the prodrug is inactive,or less active than the active compound, but may provide advantageoushandling, administration, or metabolic properties.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula—C(═O)OR wherein R is:

-   C₁₋₇alkyl (e.g., -Me,-Et,-nPr,-iPr,-nBu,-sBu,-iBu,-tBu);-   C₁₋₇aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl;    2-(4-morpholino)ethyl); and acyloxy-C₁₋₇alkyl-   (e.g., acyloxymethyl;-   acyloxyethyl;-   pivaloyloxymethyl;-   acetoxymethyl;-   1-acetoxyethyl;-   1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl;-   1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;-   1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;-   1-cyclohexyl-carbonyloxyethyl;-   cyclohexyloxy-carbonyloxymethyl;-   1-cyclohexyloxy-carbonyloxyethyl;-   (4-tetrahydropyranyloxy) carbonyloxymethyl;-   1-(4-tetrahydropyranyloxy)carbonyloxyethyl;-   (4-tetrahydropyranyl)carbonyloxymethyl; and-   1-(4-tetrahydropyranyl)carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Acronyms

For convenience, many chemical moieties are represented using well knownabbreviations, including but not limited to, methyl (Me), ethyl (Et),n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), sec-butyl (sBu),iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex),phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy(MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

For convenience, many chemical compounds are represented using wellknown abbreviations, including but not limited to, methanol (MeOH),ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), etheror diethyl ether (Et₂O), acetic acid (AcOH), dichloromethane (methylenechloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA),dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide(DMSO).

Synthesis

Methods for the chemical synthesis of compounds of the present inventionare described herein. These methods may be modified and/or adapted inknown ways in order to facilitate the synthesis of additional compoundswithin the scope of the present invention.

The compounds of the present invention may be prepared, for example, bythe methods described herein, or by adapting these or other well knownmethods in well known ways.

Synthesis: Esters

In one approach, a desired nitrile may be prepared from a simplernitrile, for example, by reaction with a halide, e.g.,1,5-dibromopentane and e.g., NaH in dimethylformamide (DMF). An exampleof such a method is illustrated in the following scheme.

The corresponding carboxylic acid then prepared from the nitrile, forexample, by reaction with NaOH and H₂O₂. An example of such a method isillustrated in the following scheme.

In another approach, a suitable carboxylic acid may be prepared, forexample, from a simpler carboxylic acid, for example, by firstprotecting the carboxylic acid and then by reaction with a halide, e.g.,1,5-dibromopentane and e.g., NaH in dimethylformamide (DMF), followed bydeprotection, e.g., by strong acid. An example of such a method isillustrated in the following scheme.

In another approach, a suitable carboxylic acid may be prepared, forexample, from a corresponding aldehyde. For example, the carboxylic acidgroup of 4-carboxybenzaldehyde is protected, for example, as atert-butyl ester, by reaction with N,N-dimethylformamide-di-tert-butylacetal. The aldehyde group is then converted to a methoxy-vinyl (enolether) group, for example, by reaction with(2-hydroxyethyl)triphenylphosphonium bromide and potassium tert-butoxidein tetrahydrofuran. The methoxy-vinyl (enol-ether) group is thenconverted to an aldehyde group, by acid hydrolysis. The aldehyde groupis then converted to a carboxylic acid group, by reaction with Jonesreagent. An example of such a method is illustrated in the followingscheme.

The resulting carboxylic acid is then further derivatised, in a methodanalogous to that described earlier. An example of such a method isillustrated in the following scheme.

The carboxylic acid is then converted to the corresponding acyl halide,e.g., acyl chloride, by reaction with, e.g., (COCl)₂. An example of sucha method is illustrated in the following scheme.

Separately, a suitable protected carbamic acid compound, also having ahydroxy group, is prepared, for example, by reaction of a suitablecarboxylic acid, for example, para-hydroxy benzoic acid, with a suitableO-substituted hydroxlyamine, such as O-benzylhydroxylamine, in thepresence of a suitable base, for exampe, dimethylaminopyridine. Anexample of such a method is illustrated in the following scheme.

Finally, the acyl halide is then reacted with the protected carbamicacid, to give the corresponding conjugate, and the carboxamic acid esteris then deprotected, e.g., with H₂ and Pd(C), to give the correspondingcarboxamic acid. An example of such a method is illustrated in thefollowing scheme.

Several additional methods for the synthesis of compounds of the presentinvention are illustrated by the following schemes.

Synthesis: Ketones

In one method, the carboxylic acid group of 4-carboxybenzaldehyde isprotected, for example, as a tert-butyl ester, by reaction withN,N-dimethylformamide-di-tert-butyl acetal. The aldehyde group is thenconverted to a methoxy-vinyl (enol ether) group, for example, byreaction with (2-hydroxyethyl)triphenylphosphonium bromide and potassiumtert-pentoxide in tetrahydrofuran. The methoxy-vinyl (enol-ether) groupis then converted to an aldehyde group, by acid hydrolysis. The aldehydegroup is then converted to a carboxylic acid group, by reaction withJones reagent. An example of such a method is illustrated in thefollowing scheme.

The carboxylic acid is then protected, for example, by reaction with3,4-dihydro-2H-pyran, in the presence of para-toluene sulfonic acid. Theprotected compound is then reacted with, for example, 1,5-dibromopentaneand sodium hydride in hexamethylphosphoramide (HMPA), to introduce a1,1-cyclohexylene group. Similar reagents may be used to introduce othercylcic groups. The carboxylic acid ester is deprotected, for example, byacid hydrolysis. The carboxylic acid group is then converted to an acidchloride, for example, by reaction with oxalyl chloride. This acidchloride is used in a later step (see below). An example of such amethod is illustrated in the following scheme.

Separately, the hydroxy group of para-hydroxy benzoic acid is convertedto an acetoxy group, for example, by reaction with acetyl chloride. Thecarboxylic acid group is then converted to an acid chloride group, forexample, by reaction with oxalyl chloride. The acid chloride is thenconverted to an O-benzylhydroxamic acid ester, for example, by reactionwith O-benzylhydroxylamine hydrochloride. An example of such a method isillustrated in the following scheme.

The O-benzylhydroxamic acid is then reacted with benzylbromide andcesium carbonate, to yield a mixture of products: an imidic acid esterand an N,O-dibenzyl hydroxamic acid. An example of such a method isillustrated in the following scheme.

The imidic acid ester is then deprotected, for example, by reaction withsodium methylate (sodium methoxide), to remove the acetoxy group andexpose hydroxy group. The hydroxy compound is then converted to a metalbromide, for example, a zinc bromide. An example of such a method isillustrated in the following scheme.

The zinc bromide compound is then reacted with the acid chloride (seeabove) to form the conjugate product. The carboxylic acid ester is thendeprotected to expose the carboxylic acid. An example of such a methodis illustrated in the following scheme.

The carboxylic acid compound is then converted to any one of a number ofalternatives. For example, it may be converted to an acid halide, forexample, an acid chloride, for example, by reaction with oxalylchloride, and then converted to, for example, an ester, an amide, aketone, etc., by reaction, for example, with an alcohol, an amine, ametal organic derivative, etc. Finally, the hydroxamic acid isdeprotected, to expose the hydroxamic acid, for example, by reactionwith H₂ and Pd(C). An example of such a method is illustrated in thefollowing scheme.

Use

The present invention provides active compounds, specifically, activecarbamic acids, as described herein.

The term “active,” as used herein, specifically includes both compoundswith intrinsic activity (drugs) as well as prodrugs of such compounds,which prodrugs may themselves exhibit little or no intrinsic activity.

The present invention also provides active compounds which inhibit HDACactivity.

The present invention also provides methods of inhibiting HDAC in acell, comprising contacting said cell with an effective amount of anactive compound. Such a method may be practised in vitro or in vivo. Inone embodiment, the method is performed in vitro. In one embodiment, themethod is performed in vivo. Preferably, the active compound is providedin the form of a pharmaceutically acceptable composition.

The term “inhibiting HDAC,” as used herein, includes: inhibiting HDACactivity; inhibiting the formation of HDAC complexes; and inhibiting theactivity of HDAC complexes.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound inhibits HDAC activity. For example, one assaywhich may conveniently be used in order to assess the HDAC inhibitionoffered by a particular compound is described in the examples below.

The present invention also provides active compounds which (a) regulate(e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression;(c) promote apoptosis; or (d) a combination of one or more of these.

Thus, the present invention also provides methods of (a) regulating(e.g., inhibiting) cell proliferation; (b) inhibiting cell cycleprogression; (c) promoting apoptosis; or (d) a combination of one ormore of these, in vitro or in vivo, comprising contacting a cell with aneffective amount of an active compound, as described herein.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound regulate (e.g., inhibit) cell proliferation,etc. For example, assays which may conveniently be used to assess theactivity offered by a particular compound are described in the examplesbelow.

For example, a sample of cells (e.g., from a tumour) may be grown invitro and an active compound brought into contact with said cells, andthe effect of the compound on those cells observed. As an example of“effect,” the morphological status of the cells (e.g., alive or dead,etc.) may be determined. Where the active compound is found to exert aninfluence on the cells, this may be used as a prognostic or diagnosticmarker of the efficacy of the compound in methods of treating a patientcarrying cells of the same cellular type.

Methods of Treatment, Etc.

The invention further provides methods of treatment, comprisingadministering to a subject in need of treatment atherapeutically-effective amount of an active compound, preferably inthe form of a pharmaceutical composition.

The invention further provides active compounds for use in a method oftreatment of the human or animal body by therapy, for example, in thetreatment of a condition mediated by HDAC, a condition known to betreated by HDAC inhibitors (such as, e.g., trichostatin A), cancer, aproliferative condition, or other condition as described herein.

The invention further provides the use of an active compound for themanufacture of a medicament, for example, for the treatment of acondition mediated by HDAC, a condition known to be treated by HDACinhibitors (such as, e.g., trichostatin A), cancer, a proliferativecondition, or other condition as described herein.

Treatment

The term “treatment,” as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,and cure of the condition. Treatment as a prophylactic measure (i.e.,prophylaxis) is also included.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of an active compound, or a material, composition or dosageform comprising an active compound, which is effective for producingsome desired therapeutic effect, commensurate with a reasonablebenefit/risk ratio.

The term “treatment” includes combination treatments and therapies, inwhich two or more treatments or therapies are combined, for example,sequentially or simultaneously. Examples of treatments and therapiesinclude, but are not limited to, chemotherapy (the administration ofactive agents, including, e.g., drugs, antibodies (e.g., as inimmunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT,ADEPT, etc.); surgery; radiation therapy; and gene therapy.

Active compounds may also be used, as described above, in combinationtherapies, that is, in conjunction with other agents, for example,cytotoxic agents.

Anti-HDAC Applications

The present invention also provides active compounds which are anti-HDACagents, and which treat a condition mediated by HDAC.

The term “a condition mediated by HDAC,” as used herein pertains to acondition in which HDAC and/or the action of HDAC is important ornecessary, e.g., for the onset, progress, expression, etc. of thatcondition, or a condition which is known to be treated by HDACinhibitors (such as, e.g., trichostatin A).

Examples of such conditions include, but are not limited to, thefollowing:

-   Cancer (see, e.g., Vigushin et al., 2001).-   Psoriasis (see, e.g., lavarone et al., 1999).-   Fibroproliferative disorders (e.g., liver fibrosis) (see, e.g., Niki    et al., 1999; Corneil et al., 1998).-   Smooth muscle proliferative disorder (e.g., atherosclerosis,    restenosis) (see, e.g., Kimura et al., 1994).-   Neurodegenative diseases (e.g., Alzheimer's, Parkinson's,    Huntington's chorea, amyotropic lateral sclerosis, spino-cerebellar    degeneration) (see, e.g., Kuusisto et al., 2001).-   Inflammatory disease (e.g., osteoarthritis, rheumatoid arthritis)    (see, e.g., Dangond et al., 1998; Takahashi et al., 1996).-   Diseases involving angiogenesis (e.g., cancer, rheumatoid arthritis,    psoriasis, diabetic retinopathy) (see, e.g., Kim et al., 2001).-   Haematopoietic disorders (e.g., anaemia, sickle cell anaemia,    thalassaeimia) (see, e.g., McCaffrey et al., 1997).-   Fungal infection (see, e.g., Bernstein et al., 2000; Tsuji et al.,    1976).-   Parasitic infection (e.g., malaria, trypanosomiasis, helminthiasis,    protozoal infections (see, e.g., Andrews et al., 2000).-   Bacterial infection (see, e.g., Onishi et al., 1996).-   Viral infection (see, e.g., Chang et al., 2000).

Conditions treatable by immune modulation (e.g., multiple sclerosis,autoimmune diabetes, lupus, atopic dermatitis, allergies, asthma,allergic rhinitis, inflammatory bowel disease; and for improvinggrafting of transplants) (see, e.g., Dangond et al., 1998; Takahashi etal., 1996).

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a condition mediated by HDAC for anyparticular cell type. For example, assays which may conveniently be usedto assess the activity offered by a particular compound are described inthe examples below.

Anticancer Applications

The present invention also provides active compounds which areanticancer agents, and treat cancer.

Thus, the present invention also provides methods of treating cancer,comprising administering to a subject in need of treatment atherapeutically-effective amount of an active compound, as describedherein, preferably in the form of a pharmaceutical composition.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a cancerous condition for any particularcell type. For example, assays which may conveniently be used to assessthe activity offered by a particular compound are described in theexamples below.

The term “anticancer agent” as used herein, pertains to a compound whichtreats a cancer (i.e., a compound which is useful in the treatment of acancer). The anti-cancer effect may arise through one or moremechanisms, including but not limited to, the regulation of cellproliferation, the inhibition of cell cycle progression, the inhibitionof angiogenesis (the formation of new blood vessels), the inhibition ofmetastasis (the spread of a tumour from its origin), the inhibition ofinvasion (the spread of tumour cells into neighbouring normalstructures), or the promotion of apoptosis (programmed cell death).Exampes of cancers are discussed below.

Antiproliferative Applications

The present invention also provides active compounds which areantiproliferative agents. The term “antiproliferative agent” as usedherein, pertain to a compound which treats a proliferative condition(i.e., a compound which is useful in the treatment of a proliferativecondition).

Thus, the present invention also provides methods of treating aproliferative condition, comprising administering to a subject in needof treatment a therapeutically-effective amount of an active compound,as described herein, preferably in the form of a pharmaceuticalcomposition.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound treats a proliferative condition for anyparticular cell type. For example, assays which may conveniently be usedto assess the activity offered by a particular compound are described inthe examples below.

The terms “cell proliferation,” “proliferative condition,”“proliferative disorder,” and “proliferative disease,” are usedinterchangeably herein and pertain to an unwanted or uncontrolledcellular proliferation of excessive or abnormal cells which isundesired, such as, neoplastic or hyperplastic growth, whether in vitroor in vivo.

Examples of proliferative conditions include, but are not limited to,benign, pre-malignant, and malignant cellular proliferation, includingbut not limited to, neoplasms and tumours (e.g., histocytoma, glioma,astrocyoma, osteoma), cancers (e.g., lung cancer, small cell lungcancer, gastrointestinal cancer, bowel cancer, colon cancer, breastcarcinoma, ovarian carcinoma, prostate cancer, testicular cancer, livercancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer,sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias,psoriasis, bone diseases, fibroproliferative disorders (e.g., ofconnective tissues), and atherosclerosis.

Any type of cell may be treated, including but not limited to, lung,gastrointestinal (including, e.g., bowel, colon), breast (mammary),ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas,brain, and skin.

Additional Uses

Active compounds may also be used as cell culture additives to inhibitHDAC, for example, in order to regulate (e.g., inhibit) cellproliferation in vitro.

Active compounds may also be used as part of an in vitro assay, forexample, in order to determine whether a candidate host is likely tobenefit from treatment with the compound in question.

Active compounds may also be used as a standard, for example, in anassay, in order to identify other active compounds, other HDACinhibitors, other anticancer agents, other antiproliferative agents,etc.

The compounds of the present invention may also be used in methods ofimproving protein production by cultured cells (see, e.g., Furukawa etal., 1998).

Routes of Administration

The active compound or pharmaceutical composition comprising the activecompound may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or topically (i.e., atthe site of desired action).

Routes of administration include, but are not limited to, oral (e.g, byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

The Subject

The subject may be a prokaryote (e.g., bacteria) or a eukaryote (e.g.,protoctista, fungi, plants, animals).

The subject may be an animal, a mammal, a placental mammal, a marsupial(e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), arodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., amouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine(e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine(e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate,simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), anape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject may be any of its forms of development, forexample, a spore, a seed, an egg, a larva, a pupa, or a foetus.

In one embodiment, the subject is a human.

Formulations

While it is possible for the active compound to be used (e.g.,administered) alone, it is often preferable to present it as aformulation.

Thus, one aspect of the present invention pertains to a compositioncomprising a compound, as described herein, and a carrier.

In one embodiment, the composition is a pharmaceutical composition(e.g., formulation, preparation, medicament) comprising a compound, asdescribed herein, and a pharmaceutically acceptable carrier.

In one embodiment, the composition is a pharmaceutical compositioncomprising at least one compound, as described herein, together with oneor more other pharmaceutically acceptable ingredients well known tothose skilled in the art, including, but not limited to,pharmaceutically acceptable carriers, diluents, excipients, adjuvants,fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers,solubilisers, surfactants (e.g., wetting agents), masking agents,colouring agents, flavouring agents, and sweetening agents.

In one embodiment, the composition further comprises other activeagents, for example, other therapeutic or prophylactic agents.

Suitable carriers, diluents, excipients, etc. can be found in standardpharmaceutical texts. See, for example, Handbook of PharmaceuticalAdditives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (SynapseInformation Resources, Inc., Endicott, N.Y., USA), Remington'sPharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton,Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

Another aspect of the present invention pertains to methods of making apharmaceutical composition comprising admixing at least one activecompound, as defined above, together with one or more otherpharmaceutically acceptable ingredients well known to those skilled inthe art, e.g., carriers, diluents, excipients, etc. If formulated asdiscrete units (e.g., tablets, etc.), each unit contains a predeterminedamount (dosage) of the active compound.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, ingredients, materials, compositions, dosage forms, etc.,which are, within the scope of sound medical judgment, suitable for usein contact with the tissues of the subject in question (e.g., human)without excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio. Each carrier, diluent, excipient, etc. must also be “acceptable”in the sense of being compatible with the other ingredients of theformulation.

The formulations may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association theactive compound with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active compound with carriers(e.g., liquid carriers, finely divided solid carrier, etc.), and thenshaping the product, if necessary.

The formulation may be prepared to provide for rapid or slow release;immediate, delayed, timed, or sustained release; or a combinationthereof.

Formulations may suitably be in the form of liquids, solutions (e.g.,aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous),emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups,electuaries, mouthwashes, drops, tablets (including, e.g., coatedtablets), granules, powders, lozenges, pastilles, capsules (including,e.g., hard and soft gelatin capsules), cachets, pills, ampoules,boluses, suppositories, pessaries, tinctures, gels, pastes, ointments,creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster,bandage, dressing, or the like which is impregnated with one or moreactive compounds and optionally one or more other pharmaceuticallyacceptable ingredients, including, for example, penetration, permeation,and absorption enhancers. Formulations may also suitably be provided ina the form of a depot or reservoir.

The active compound may be dissolved in, suspended in, or admixed withone or more other pharmaceutically acceptable ingredients. The activecompound may be presented in a liposome or other microparticulate whichis designed to target the active compound, for example, to bloodcomponents or one or more organs.

Formulations suitable for oral administration (e.g, by ingestion)include liquids, solutions (e.g., aqueous, non-aqueous), suspensions(e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water,water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders,capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes,lozenges, pastilles, as well as patches, adhesive plasters, depots, andreservoirs. Lozenges typically comprise the active compound in aflavored basis, usually sucrose and acacia or tragacanth. Pastillestypically comprise the active compound in an inert matrix, such asgelatin and glycerin, or sucrose and acacia. Mouthwashes typicallycomprise the active compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets,lozenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters,depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),suppositories, pessaries, gels, pastes, ointments, creams, lotions,oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels,pastes, ointments, creams, lotions, and oils, as well as patches,adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression or molding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the active compoundin a free-flowing form such as a powder or granules, optionally mixedwith one or more binders (e.g., povidone, gelatin, acacia, sorbitol,tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g.,lactose, microcrystalline cellulose, calcium hydrogen phosphate);lubricants (e.g., magnesium stearate, talc, silica); disintegrants(e.g., sodium starch glycolate, cross-linked povidone, cross-linkedsodium carboxymethyl cellulose); surface-active or dispersing or wettingagents (e.g., sodium lauryl sulfate); preservatives (e.g., methylp-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours,flavour enhancing agents, and sweeteners. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active compound therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile. Tablets may optionally be provided with acoating, for example, to affect release, for example an enteric coating,to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the active compound and aparaffinic or a water-miscible ointment base.

Creams are typically prepared from the active compound and anoil-in-water cream base. If desired, the aqueous phase of the cream basemay include, for example, at least about 30% w/w of a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active compound through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogues.

Emulsions are typically prepared from the active compound and an oilyphase, which may optionally comprise merely an emulsifier (otherwiseknown as an emulgent), or it may comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabiliser. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabiliser(s) make up the so-called emulsifying wax, and the waxtogether with the oil and/or fat make up the so-called emulsifyingointment base which forms the oily dispersed phase of the creamformulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulphate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the active compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or other mineral oils canbe used.

Formulations suitable for intranasal administration, where the carrieris a liquid, include, for example, nasal spray, nasal drops, or byaerosol administration by nebuliser, include aqueous or oily solutionsof the active compound.

Formulations suitable for intranasal administration, where the carrieris a solid, include, for example, those presented as a coarse powderhaving a particle size, for example, in the range of about 20 to about500 microns which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalationor insufflation therapy) include those presented as an aerosol sprayfrom a pressurised pack, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye dropswherein the active compound is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active compound.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols, for example,cocoa butter or a salicylate; or as a solution or suspension fortreatment by enema.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active compound, such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the activecompound is dissolved, suspended, or otherwise provided (e.g., in aliposome or other microparticulate). Such liquids may additional containother pharmaceutically acceptable ingredients, such as anti-oxidants,buffers, preservatives, stabilisers, bacteriostats, suspending agents,thickening agents, and solutes which render the formulation isotonicwith the blood (or other relevant bodily fluid) of the intendedrecipient. Examples of excipients include, for example, water, alcohols,polyols, glycerol, vegetable oils, and the like. Examples of suitableisotonic carriers for use in such formulations include Sodium ChlorideInjection, Ringer's Solution, or Lactated Ringer's Injection. Typically,the concentration of the active compound in the liquid is from about 1ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1μg/ml. The formulations may be presented in unit-dose or multi-dosesealed containers, for example, ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriatedosages of the active compounds, and compositions comprising the activecompounds, can vary from patient to patient. Determining the optimaldosage will generally involve the balancing of the level of therapeuticbenefit against any risk or deleterious side effects. The selecteddosage level will depend on a variety of factors including, but notlimited to, the activity of the particular compound, the route ofadministration, the time of administration, the rate of excretion of thecompound, the duration of the treatment, other drugs, compounds, and/ormaterials used in combination, the severity of the condition, and thespecies, sex, age, weight, condition, general health, and prior medicalhistory of the patient. The amount of compound and route ofadministration will ultimately be at the discretion of the physician,veterinarian, or clinician, although generally the dosage will beselected to achieve local concentrations at the site of action whichachieve the desired effect without causing substantial harmful ordeleterious side-effects.

Administration can be effected in one dose, continuously orintermittently (e.g., in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell(s) being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician, veterinarian, or clinician.

In general, a suitable dose of the active compound is in the range ofabout 0.1 to about 250 mg per kilogram body weight of the subject perday. Where the active compound is a salt, an ester, an amide, a prodrug,or the like, the amount administered is calculated on the basis of theparent compound and so the actual weight to be used is increasedproportionately.

Kits

One aspect of the invention pertains to a kit comprising (a) the activeingredient, preferably provided in a suitable container and/or withsuitable packaging; and (b) instructions for use, for example, writteninstructions on how to administer the active compound, etc.

The written instructions may also include a list of indications forwhich the active ingredient is a suitable treatment.

EXAMPLES

The following are examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

General

¹H NMR spectra were recorded at ambient temperature with WH-90/DS orMercury 200 (Varian) spectrometers. The HPLC measurements were performedon a Gilson Model 302 system equipped with a spectrophotometer.Elemental analyses were obtained with a Carlo Erba EA 1108 instrument.Melting points were measured on a “Boëtius” micro melting pointapparatus and are uncorrected. Silicagel, 0.035-0.070 mm, (Acros) wasemployed for column chromatography. All the solvents were purifiedbefore use by routine techniques. To isolate reaction products thesolvents were removed by evaporation using a vacuum rotary evaporator,the water bath temperature not exceeding 40° C.

Various reagents were purchased from Sigma-Aldrich (The Old Brickyard,New Road, Gillingham, Dorset, UK), Acros Organics (JanssensPharmaceuticalaan 3A, 2440 Geel, Belgium), and Fluka (Industriestr. 25,9470 Buchs, Switzerland).

The following reagents were prepared according to procedures describedin literature: 2.46 N potassium 2-methyl-2-butanolate solution intetrahydrofuran (Tedesco, R.; Fiaschi, R.; Napolitano, E. Synthesis1995, 1493), tert-butyl 4-formylbenzoate (6b) (Pritchard, G. J. et al J.Med. Chem. 2001, 44, 1491).

Example 1 1-(4-Methoxyphenyl)cyclohexanecarbonitrile (E2)

To a solution of 4-methoxyphenylacetonitrile (E1) (1.002 g, 6.8 mmol)and 1,5-dibromopentane (1.886 g, 8.2 mmol) in dry dimethylformamide (15ml) at ice bath temperature slowly (ca. 2-3 minutes) a 60% suspension ofNaH in mineral oil (0.579 g, 14.4 mmol) was added. The obtained reactionmixture was stirred for 15 minutes at ice bath temperature and for 1.5hours at room temperature, then the contents were poured into benzene(75 ml). The mixture was successively washed with water (3×75 ml), brine(25 ml), and dried (Na₂SO₄). The solvent was evaporated and the residuewas chromatographed on silicagel (50 g) with petroleum ether-ethylacetate (5:1) as eluent to give the title compound (0.924 g, 63%) as awhite solid. ¹H NMR (CDCl₃, HMDSO) δ: 1.00-2.28 (10H, m); 3.81 (3H, s);6.90 (2H, d, J=9.0 Hz); 7.40 (2H, d, J=9.0 Hz).

Example 2 1-(4-Methoxyphenyl)cyclohexanecarboxylic acid (E3)

A solution of 1-(4-methoxyphenyl)cyclohexanecarbonitrile (E2) (1.092 g,5.07 mmol) in dioxane (6 ml) to a mixture of 2 M NaOH in water (150 ml)and 30% H₂O₂ in water (7.5 ml) was added and the resultant suspensionwas stirred under reflux for 4 days. The pH of the reaction medium wasbrought to pH 1 with conc. HCl (ca. 30 ml) and the obtained mixture wasextracted with ethyl acetate (4×80 ml). The combined organic extract waswashed with brine (50 ml) and dried (Na₂SO₄). The solvent was evaporatedand the residue was chromatographed on silicagel (50 g) withbenzene-ethyl acetate-acetic acid (9:1:0.15) as eluent affording thetitle compound (0.844 g, 71%) as a white solid. ¹H NMR (CDCl₃, HMDSO) δ:1.05-1.91 (8H, m); 2.16-2.61 (2H, m); 3.76 (3H, s); 6.86 (2H, d, J=9.0Hz); 7.34 (2H, d, J=9.0 Hz); 11.26 (1H, br s).

Example 3 Tetrahydro-2H-pyran-2-yl 2-phenylacetate (E5)

To a saturated solution of anhydrous p-toluenesulphonic acid in drydichloromethane (25 ml), phenylacetic acid (E4) (0.581 g, 4.26 mmol) and3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were successively added, and theresultant solution was stirred for 1 hour at room temperature. To thereaction mixture, triethylamine (1 ml, 7.2 mmol) was added, and thevolatiles were evaporated. The crude title compound was obtained and wasimmediately utilized in the next step of the synthesis.

Example 4 1-Phenylcyclohexanecarboxylic acid (E7)

The crude tetrahydro-2H-pyran-2-yl 2-phenylacetate (E5) (0.581 g, 4.26mmol)) and 1,5-dibromopentane (1.474 g, 6.41 mmol) were dissolved in dryhexamethylphosphoric triamide (6 ml) and the mixture was cooled in anice bath. To the cooled solution 60% suspension of NaH in mineral oil(0.507 g, 12.67 mmol) was added and the reaction mixture was stirred atice bath temperature for 15 minutes and at room temperature for 5 hours.The reaction mixture was diluted with dioxane (20 ml) and water (15 ml),and the pH of the reaction medium was brought to pH 1 with conc. HCl (3ml). The reaction mixture was stirred for 20 minutes and poured intoethyl acetate (75 ml). The organic layer was washed with a mixture of 2N HCl and brine, 1:1 (2×50 ml), brine (50 ml), and dried (Na₂SO₄). Thesolvents were evaporated and the residue was chromatographed onsilicagel (50 g) with benzene-ethyl acetate-acetic acid (9:1:0.1) aseluent to give a crude product. The product was re-chromatographed onsilicagel (50 g) with petroleum ether-ethyl acetate-acetic acid(8:2:0.1) as eluent to give the title compound (0.414 g, 47% based onE4) as a white solid. ¹H NMR (CDCl₃, HMDSO) δ: 1.04-2.01 (8H, m);2.19-2.62 (2H, m); 7.09-7.55 (5H, m), 10.29 (1H, br s).

Example 5 Methyl 4-(2-methoxyethenyl)benzoate (E9)

To a suspension of (methoxymethyl)triphenylphosphonium chloride (6.366g, 18.5 mmol) in dry tetrahydrofuran (50 ml) under argon atmosphere at−78° C. slowly (ca. for 5 minutes) a 2.46 N solution of potassiumtert-butoxide in tetrahydrofuran (8.2 ml, 20.2 mmol) was added and thereaction mixture was stirred at this temperature for 1 hour. A solutionof methyl 4-formylbenzoate (E8) (2.531 g, 15.4 mmol) in tetrahydrofuran(10 ml) was added to the reaction mixture and the resultant suspensionwas stirred at −78° C. for 30 minutes. The cooling bath was removed andthe reaction was stirred for 30 minutes allowing to warm up to roomtemperature. The reaction mixture was partitioned between benzene (150ml) and water (150 ml), and the organic layer was washed successivelywith water (150 ml), brine (50 ml), and dried (Na₂SO₄). The solvent wasevaporated and the residue was chromatographed on silicagel (100 g) withtoluene-triethylamine (100:0.25) as eluent to give the title compound(2.696 g, 91%) as a mixture of E and Z isomers (ca. 95:5). (E)-(E9): ¹HNMR (CDCl₃, HMDSO) δ: 3.67 (3H, s); 3.86 (3H, s); 5.81 (1H, d, J=13.5Hz); 7.14 (1H, d, J=13.5 Hz); 7.25 (2H, d, J=8.5 Hz); 7.89 (2H, d, J=8.5Hz). A small additional singlet at 3.80 ppm and 2 doublets at 5.23 (d,J=7.6 Hz); 6.22 ppm (d, J=7.6 Hz) in the ¹H NMR spectrum of E9 wasattributed to minor amounts (ca. 5%) of (Z)-(E9) isomer present in theproduct.

Example 6 2-[4-(Methoxycarbonyl)phenyl]acetic acid (E11)

To a solution of methyl 4-(2-methoxyethenyl)benzoate (E9) (2.41 g, 12.5mmol) in dioxane (50 ml) 1N water solution of HCl (40 ml) was added andthe resultant mixture was stirred at room temperature for 12 hours. Thereaction mixture was extracted with ethyl acetate (3×50 ml), the organicextracts were combined, washed with brine (2×30 ml), and dried (Na₂SO₄).The solvents were evaporated, the residue was dissolved in acetone (70ml) and cooled to −50° C. To the cold solution at this temperatureslowly (ca. for 5 minutes) 2.67 M Jones reagent (CrO₃/H₂SO₄; 7.5 ml,20.0 mmol) was added and the obtained mixture was stirred at −40 to −50°C. for 1 hour and at −30° C. for 20 minutes. Isopropyl alcohol (2 ml)was added to the reaction mixture and the cooling bath was removedallowing the reaction to warm up for 10 minutes. The mixture was pouredinto water (150) and extracted with ethyl acetate (3×100 ml). Theorganic layers were combined, washed with brine (2×50), and dried(Na₂SO₄). The solvent was evaporated and the residue was dissolved in asmall amount of hot dioxane (1-2 ml). Addition of petroleum ether (4-6ml) caused the formation of a precipitate. The mixture was filtered andthe precipitate was washed with dioxane-petroleum ether (1:4). Thefiltrate was evaporated and the precipitate formation procedure wasrepeated as described above. Then the filtrate was evaporated and theresidue was chromatographed on silicagel (100 g) with petroleumether-dioxane-acetic acid (2.5:7.5:0.1) to give the title compound(0.681 g, 28%) as a white solid. ¹H NMR (CDCl₃, HMDSO) δ: 3.68 (2H, s);3.89 (3H, s); 7.33 (2H, d, J=8.2 Hz); 7.97 (2H, d, J=8.2 Hz); 10.82 (1H,br s).

Example 7 Methyl 4-[2-oxo-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]benzoate(E12)

To a saturated solution of anhydrous p-toluenesulphonic acid in drydichloromethane (35 ml) successively 2-[4-(methoxycarbonyl)phenyl]aceticacid (E11) (0.671 g, 3.45 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9mmol) were added, and the resultant solution was stirred for 45 minutesat room temperature. To the reaction mixture triethylamine (1 ml, 7.2mmol) was added and the volatiles were evaporated. The obtained crudetitle product (1.64 g) was immediately utilized in the next step of thesynthesis.

Example 8 1-[4-(Methoxycarbonyl)phenyl]cyclohexanecarboxylic acid (E14)

The crude methyl 4-[2-oxo-2-(tetrahydro-2H-pyran-2-yl-oxy)ethyl]benzoate(E12) (1.64 g) (0.671 g, 3.45 mmol)) and 1,5-dibromopentane (1.200 g,5.21 mmol) were dissolved in dry hexamethylphosphoric triamide (6 ml)and the mixture was cooled in an ice bath. To the cooled solution, a 60%suspension of NaH in mineral oil (0.425 g, 10.62 mmol) was added and thereaction mixture was stirred at ice bath temperature for 15 minutes and1.5 hours at room temperature. The reaction mixture was diluted withdioxane (20 ml) and water (15 ml), and the pH of the medium was broughtto pH 1 with conc. HCl (3 ml). The reaction mixture was stirred for 20minutes and poured into ethyl acetate (100 ml). The organic layer waswashed with 2N HCl (2×50 ml), brine (50 ml), and dried (Na₂SO₄). Thesolvents were evaporated and the residue was chromatographed onsilicagel (50 g) with toluene-ethyl acetate-acetic acid (8:2:0.1) aseluent to give the title compound (0.621 g, 68.5% based on E11) as awhite solid. ¹H NMR (CDCl₃, HMDSO) δ: 0.94-2.09 (8H, m); 2.25-2.65 (2H,m); 3.88 (3H, s); 7.49 (2H, d, J=8.6 Hz); 7.96 (2H, d, J=8.6 Hz); 10.07(1H, br s).

Example 9 1-(4-Methoxyphenyl)cyclohexanecarbonyl chloride (E15)

To a solution of 1-(4-methoxyphenyl)-cyclohexanecarboxylic acid (E3)(0.075 g, 0.32 mmol) in dry dichloromethane (2 ml) under argonatmosphere at ice bath temperature oxalyl chloride (0.327 g, 2.57 mmol)and one drop of dimethylformamide were added. The reaction mixture wasstirred at room temperature for 15 minutes and at 40° C. for one hour,then concentrated under reduced pressure to give crude title product(0.082 g, ca. 100%). The crude product was immediately utilized in thenext step of the synthesis without further purification.

Example 10 1-Phenylcyclohexanecarbonyl chloride (E16)

To a solution of 1-phenylcyclohexanecarboxylic acid (E7) (0.095 g, 0.46mmol) in dry dichloromethane (3 ml) under argon atmosphere at ice bathtemperature oxalyl chloride (0.468 g, 3.68 mmol) and one drop ofdimethylformamide were added. The reaction mixture was stirred at roomtemperature for 15 minutes and at 40° C. for one hour, then concentratedunder reduced pressure to give crude title compound (0.105 g, ca. 100%).The crude product was immediately utilized in the next step of thesynthesis without further purification.

Example 11 Methyl 4-[1-(chlorocarbonyl)cyclohexyl]benzoate (E17)

To a solution of 1-[4-(methoxycarbonyl)phenyl]-cyclohexanecarboxylicacid (E14) (0.174 g, 0.66 mmol) in dry dichloromethane (4 ml) underargon atmosphere at ice bath temperature oxalyl chloride (0.648 g, 5.10mmol) and one drop of dimethylformamide were added. The reaction mixturewas stirred at room temperature for 15 minutes and at 40° C. for onehour, then concentrated under reduced pressure to give crude titlecompound (0.187 g, ca. 100%). The crude product was immediately utilizedin the next step of the synthesis without further purification.

Example 12 N-(Benzyloxy)₄-hydroxybenzamide (E20)

To a mixture of 4-hydroxybenzoic acid (E18) (0.424 g, 3.07 mmol),O-benzylhydroxylamine hydrochloride (E19) (0.490 g, 3.07 mmol), and4-dimethylaminopyridine (0.414 g, 3.39 mmol) in dichloromethane (30 ml)under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.643 g, 3.35 mmol) was added and the resultant mixturewas stirred at room temperature for 5 hours. The reaction mixture waspoured into a mixture of saturated NaH₂PO₄ (30 ml) and water (70 ml),and extracted with ethyl acetate (2×75 ml). The extract was washed witha mixture of saturated NaH₂PO₄ (15 ml) and water (35 ml), brine (50 ml),and dried (MgSO₄). The solvent was evaporated and the residue waschromatographed on silicagel (50 g) with benzene-ethyl acetate-aceticacid (75:25:1, 100 ml) and benzene-ethyl acetate-acetic acid (50:50:1,300 ml) as eluents to give the title compound (0.338 g, 45%) as a whitesolid. ¹H NMR (DMSO-d₆, HMDSO), δ: 4.88 (2H, s); 6.79 (2H, d, J=8.8 Hz);7.23-7.55 (5H, m); 7.59 (2H, d, J=8.8 Hz); 10.02 (1H, br s); 11.48 (1H,s).

Example 13 4-{[(Benzyloxy)amino]carbonyl}phenyl1-(4-methoxyphenyl)cyclohexanecarboxylate (E21)

To a solution of N-(benzyloxy)-4-hydroxybenzamide (E20) (0.078 g, 0.32mmol) and 4-dimethylaminopyridine (0.047 g, 0.38 mmol) intetrahydrofuran (2 ml) under argon atmosphere at ice bath temperature asolution of 1-(4-methoxyphenyl) cyclohexanecarbonyl chloride (E15)(0.082 g, obtained in the preceding step of the synthesis) intetrahydrofuran (2 ml) was added. The resultant white suspension wasstirred at room temperature overnight and poured into ethyl acetate (80ml). The ethyl acetate extract was washed with water (50 ml), brine (30ml), and dried (Na₂SO₄). The solvent was evaporated and the residue wasdissolved in a small amount of benzene (0.5-1 ml). The precipitatedsolid was filtered off, the filtrate was evaporated and chromatographedon silicagel (10 g) with benzene-ethyl acetate (9:1) as eluent affordingthe title compound (0.077 g, 52% based on E3) as a white solid. ¹H NMR(DMSO-d₆, HMDSO), δ: 1.07-2.01 (8H, m); 2.21-2.61 (2H, m, overlappedwith a signal of DMSO); 3.75 (3H, s); 4.92 (2H, s); 6.97 (2H, d, J=8.5Hz); 7.04 (2H, d, J=8.2 Hz); 7.23-7.54 (7H, m); 7.76 (2H, d, J=8.5 Hz);11.77 (1H, s).

Example 14 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-methoxyphenyl)-cyclohexanecarboxylate (E24) (PX118478)

A mixture of 4-{[(benzyloxy)amino]carbonyl}phenyl 1-(4-methoxyphenyl)cyclohexanecarboxylate (E21) (0.072 g, 0.16 mmol) and 5% palladium onactivated carbon (0.054 g) in methanol (1 ml) was hydrogenated at roomtemperature for 45 minutes. The black suspension was filtered, thecatalyst was washed with methanol (3×1 ml), and the filtrate wasevaporated to give a white solid. The solid was suspended in diethylether (3 ml) and the mixture was intensively stirred overnight. Thesolid was filtered, washed with diethyl ether (1 ml), and dried invacuum to give the title compound (0.037 g, 64%) as white crystals, m.p.127-129° C. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.18-1.90 (8H, m); 2.36-2.65(2H, m, overlapped with a signal of DMSO); 3.76 (3H, s); 6.97 (2H, d,J=8.6 Hz); 7.01 (2H, d, J=8.8 Hz); 7.40 (2H, d, J=8.8 Hz); 7.77 (2H, d,J=8.6 Hz); 9.07 (1H, br s); 11.23 (1H, br s). HPLC analysis on SymmetryC₈ column: impurities 2.2% (column size 3.9×150 mm; mobile phaseacetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV 230 nm;sample concentration 0.3 mg/ml; flow rate 1.0 ml/min). Anal. Calcd forC₂₁H₂₃NO₅*0.3H₂O, %: C, 67.29; H, 6.35; N, 3.74. Found, %: C, 67.29; H,6.23; N, 3.76.

Example 15 4-{[(Benzyloxy)amino]carbonyl}phenyl1-phenylcyclohexanecarboxylate (E22)

To a solution of N-(benzyloxy)-4-hydroxybenzamide (E20) (0.100 g, 0.41mmol) and 4-dimethylaminopyridine (0.056 g, 0.46 mmol) intetrahydrofuran (4 ml) under argon atmosphere at ice bath temperature asolution of 1-phenylcyclohexanecarbonyl chloride (E16) (0.105 g,obtained in the preceding step of the synthesis) in tetrahydrofuran (2ml) was added. The resultant white suspension was stirred at roomtemperature overnight and poured into ethyl acetate (100 ml). The ethylacetate extract was washed with water (50 ml), brine (30 ml), and dried(Na₂SO₄). The solvent was evaporated and the residue was chromatographedon silicagel (10 g) with benzene-ethyl acetate (9:1) as eluent affordingthe title compound (0.057 g, 32% based on E20) as a white solid. ¹H NMR(DMSO-d₆, HMDSO), δ: 1.05-2.01 (8H, m); 2.23-2.61 (2H, m, overlappedwith a signal of DMSO); 4.92 (2H, s); 7.06 (2H, d, J=8.6 Hz); 7.25-7.59(10H, m); 7.77 (2H, m); 11.78 (1H, s).

Example 16 4-[(Hydroxyamino)carbonyl]phenyl1-phenylcyclohexanecarboxylate (E25) (PX118479)

A mixture of 4-{[(benzyloxy)amino]carbonyl}phenyl1-phenylcyclohexane-carboxylate (E22) (0.054 g, 0.125 mmol) and 5%palladium on activated carbon (0.038 g) in methanol (1 ml) washydrogenated at room temperature for 45 minutes. The black suspensionwas filtered, the catalyst was washed with methanol (3×1 ml), and thefiltrate was evaporated and dried in vacuum to give the title compound(0.038 g, 89%) as white crystals, m.p. 142-144° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 1.16-1.94 (8H, m); 2.35-2.64 (2H, m, overlapped with a signalof DMSO); 7.02 (2H, d, J=8.7 Hz); 7.26-7.54 (5H, m); 7.77 (2H, d, J=8.7Hz); 9.06 (1H, s); 11.24 (1H, br s). HPLC analysis on Symmetry C₈column: impurities 2% (column size 3.9×150 mm; mobile phaseacetonitrile−0.1M phosphate buffer (pH 2.5), 50:50; detector UV 230 nm;sample concentration 0.5 mg/ml; flow rate 1.1 ml/min). Anal. Calcd forC₂₀H₂₁NO₄*0.4H₂O, %: C, 69.31; H, 6.34; N, 4.04. Found, %: C, 69.36; H,6.24; N, 3.97.

Example 17 Methyl 4-{1-[(4-{[(benzyloxy)amino]carbonyl}phenoxy)carbonyl]cyclohexyl}benzoate

To a solution of N-(benzyloxy)-4-hydroxybenzamide (E20) (0.150 g, 0.61mmol) and 4-dimethylaminopyridine (0.083 g, 0.68 mmol) intetrahydrofuran (6 ml) under argon atmosphere at ice bath temperature asolution of methyl 4-[1-(chlorocarbonyl)cyclohexyl]benzoate (E17) (0.187g, obtained in the preceding step of the synthesis) in tetrahydrofuran(2 ml) was added. The resultant white suspension was stirred at roomtemperature overnight and poured into ethyl acetate (150 ml). The ethylacetate extract was washed with water (70 ml), brine (30 ml), and dried(Na₂SO₄). The solvent was evaporated and the residue was twicechromatographed on silicagel (10 g) with petroleum ether-ethyl acetate(8:2) and (7:3) as eluents affording the title compound (0.066 g, 22%based upon E20) as a white solid. ¹H NMR (DMSO-d₆, HMDSO), δ: 1.05-2.03(8H, m); 2.25-2.69 (2H, m, overlapped with a signal of DMSO); 3.85 (3H,s); 4.92 (2H, s); 7.07 (2H, d, J=8.6 Hz); 7.29-7.52 (5H, m); 7.65 (2H,d, J=8.3 Hz); 7.77 (2H, d, J=8.6 Hz); 8.02 (2H, d, J=8.3 Hz); 11.79 (1H,br s).

Example 18 Methyl 4-[1-({4-[(hydroxyamino)carbonyl]phenoxy}carbonyl)-cyclohexyl]benzoate (E26) (PX118480)

A mixture of methyl4-{1-[(4-{[(benzyloxy)amino]carbonyl}phenoxy)carbonyl]cyclohexyl)-benzoate (E23) (0.063 g, 0.129 mmol) and 5% palladium onactivated carbon (0.026 g) in methanol (1 ml) was hydrogenated at roomtemperature for 50 minutes. The black suspension was filtered, thecatalyst was washed with methanol (3×1 ml), and the filtrate wasevaporated to give a viscous oil. The oil was converted to whitecrystals by stirring in diethyl ether (3 ml) overnight. The solid wasfiltered, washed with diethyl ether (0.5 ml), and dried in vacuum togive the title compound (0.033 g, 64%) as white crystals, m.p. 129-131°C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.13-1.99 (8H, m); 2.35-2.58 (2H, m,overlapped with a signal of DMSO); 3.86 (3H, s); 7.05 (2H, d, J=8.6 Hz);7.65 (2H, d, J=8.4 Hz); 7.77 (2H, d, J=8.6 Hz); 8.01 (2H, d, J=8.4 Hz);9.07 (1H, s); 11.25 (1H, s). HPLC analysis on Symmetry C₈ column:impurities 2.5% (column size 3.9×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 60:40; detector UV 254 nm; sampleconcentration 0.5 mg/ml; flow rate 1.0 ml/min). Anal. Calcd forC₂₂H₂₃NO₆*0.35H₂O, %: C, 65.45; H, 5.92; N, 3.47. Found, %: C, 65.17; H,5.76; N, 3.49.

Example 19 1-(4-Methoxyphenyl)cyclohexanecarbonitrile (3a)

To a solution of 4-methoxyphenylacetonitrile (2) (1.002 g, 6.8 mmol) and1,5-dibromopentane (1.886 g, 8.2 mmol) in dry dimethylformamide (15 ml)at ice bath temperature slowly (ca. 2-3 min.) a 60% suspension of NaH inmineral oil (0.579 g, 14.4 mmol) was added. The obtained reactionmixture was stirred for 15 minutes at ice bath temperature and for 1.5hours at room temperature, then the content was poured into benzene (75ml). The mixture was successively washed with water (3×75 ml), brine (25ml), and dried (Na₂SO₄). The solvent was evaporated and the residue waschromatographed on silica gel (50 g) with petroleum ether-ethyl acetate(5:1) as eluent to give the title compound (0.924 g, 63%) as a whitesolid. ¹H NMR (CDCl₃, HMDSO) δ: 1.00-2.28 (10H, m); 3.81 (3H, s); 6.90(2H, d, J=9.0 Hz); 7.40 (2H, d, J=9.0 Hz).

Example 20 1-(4-Methoxyphenyl)cyclopentanecarbonitrile (3b)

The title compound was obtained from 4-methoxyphenylacetonitrile (2) and1,4-dibromobutane by the method of the previous example, yield 80%. ¹HNMR (CDCl₃, HMDSO) δ: 1.61-2.68 (8H, m); 3.79 (3H, s); 6.89 (2H, d,J=9.2 Hz); 7.34 (2H, d, J=9.2 Hz).

Example 21 1-(4-Methoxyphenyl)cyclohexanecarboxylic acid (1/1)

A solution of 1-(4-methoxyphenyl)cyclohexanecarbonitrile (6) (1.092 g,5.07 mmol) in dioxane (6 ml) was added to a mixture of 2M NaOH in water(150 ml) and 30% H₂O₂ in water (7.5 ml) was added and the resultantsuspension was stirred under reflux for 4 days. The pH of the reactionmedium was brought to pH 1 with conc. HCl (ca. 30 ml) and the obtainedmixture was extracted with ethyl acetate (4×80 ml). The combined organicextract was washed with brine (50 ml) and dried (Na₂SO₄). The solventwas evaporated and the residue was chromatographed on silica gel (50 g)with benzene-ethyl acetate-acetic acid (9:1:0.15) as eluent affordingthe title compound (0.844 g, 71%) as a white solid. ¹H NMR (CDCl₃,HMDSO) δ: 1.05-1.91 (8H, m); 2.16-2.61 (2H, m); 3.76 (3H, s); 6.86 (2H,d, J=9.0 Hz); 7.34 (2H, d, J=9.0 Hz); 11.26 (1H, br s).

Example 22 1-(4-Methoxyphenyl)-cyclopentanecarboxylic acid (1/2)

The title compound was obtained from1-(4-methoxyphenyl)cyclohexanecarbonitrile (3b) by the method of theprevious example, yield 64%. ¹H NMR (CDCl₃, HMDSO) δ: 1.48-2.14 (6H, m);2.37-2.82 (2H, m); 3.76 (3H, s); 6.84 (2H, d, J=9.0 Hz); 7.28 (2H, d,J=9.0 Hz); 9.12 (1H, br s).

Example 23 Tetrahydro-2H-pyran-2-yl 2-phenylacetate (5a)

To a saturated solution of anhydrous p-toluenesulphonic acid in drydichloromethane (25 ml) successively phenylacetic acid (4a) (0.581 g,4.26 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were added, andthe resultant solution was stirred at room temperature until thestarting material 4a disappeared (ca. 1 hour). To the reaction mixturetriethylamine (1 ml, 7.2 mmol) was added and the volatiles wereevaporated. The obtained crude tetrahydro-2H-pyran-2-yl 2-phenylacetate(5a) was immediately utilized in the next step of the synthesis.

Example 24 1-Phenylcyclohexanecarboxylic acid (1/3)

The crude tetrahydro-2H-pyran-2-yl 2-phenylacetate (5a) and1,5-dibromopentane (1.474 g, 6.41 mmol) were dissolved in dryhexamethylphosphoric triamide (6 ml) and the mixture was cooled in anice bath. To the cooled solution 60% suspension of NaH in mineral oil(0.507 g, 12.67 mmol) was added and the reaction mixture was stirred atice bath temperature for 15 minutes and at room temperature for 5 hours.The reaction mixture was diluted with dioxane (20 ml) and water (15 ml),and the pH of the reaction medium was brought to pH 1 with conc. HCl (3ml). The reaction mixture was stirred for 20 minutes and poured intoethyl acetate (75 ml). The organic layer was washed with a mixture of 2N HCl and brine, 1:1 (2×50 ml), brine (50 ml), and dried (Na₂SO₄). Thesolvents were evaporated and the residue was chromatographed on silicagel (50 g) with benzene-ethyl acetate-acetic acid (9:1:0.1) as eluent togive a crude product. The product was re-chromatographed on silica gel(50 g) with petroleum ether-ethyl acetate-acetic acid (8:2:0.1) aseluent to give the title compound (0.414 g, 47% based on 4a) as a whitesolid. ¹H NMR (CDCl₃, HMDSO) δ: 1.04-2.01 (8H, m); 2.19-2.62 (2H, m);7.09-7.55 (5H, m), 10.29 (1H, br s).

Example 25 1-(4-ethoxyphenyl)cyclohexanecarboxylic acid (1/5),

The title compound was obtained in a manner analogous to that for1-Phenylcyclohexanecarboxylic acid (1/3) starting with(4-ethoxyphenyl)acetic acid (4b), via tetrahydro-2H-pyran-2-yl2-(4-ethoxyphenyl)acetate (5b). The crude product 1/5 waschromatographed on silica gel with toluene-ethyl acetate-acetic acid(9:1:0.1) as eluent to give 1-(4-ethoxyphenyl)cyclohexanecarboxylic acid(1/5) in 40% yield. ¹H NMR (CDCl₃, HMDSO) δ: ¹H NMR (CDCl₃, HMDSO) δ:1.17-2.08 (8H, m); 1.34 (3H, t, J=7.0 Hz); 2.26-2.63 (2H, m); 4.02 (2H,q, J=7.0 Hz); 6.88 (2H, d, J=8.8 Hz); 7.36 (2H, d, J=8.8 Hz); 10.09 (1H,br s).

Example 26 1-[1,1′-biphenyl]-4-ylcyclohexanecarboxylic acid (1/8),

The title compound was obtained in a manner analogous to that for1-Phenylcyclohexanecarboxylic acid (1/3) starting with(1,1′-biphenyl)acetic acid (4c), via tetrahydro-2H-pyran-2-yl2-(1,1′-biphenyl)acetate (5c). The crude product 1/8 was chromatographedon silica gel with toluene-ethyl acetate-acetic acid (9:1:0.1) as eluentto give 1-[1,1′-biphenyl]-4-ylcyclohexanecarboxylic acid (1/8) in 25%yield. ¹H NMR (CDCl₃, HMDSO) δ: 1.01-2.08 (8H, m); 2.23-2.67 (2H, m);7.14-7.79 (9H, m); 10.21 (1H, br s).

Example 27 1-(4-bromophenyl)-cyclohexanecarboxylic acid (1/9)

The title compound was obtained in a manner analogous to that for1-Phenylcyclohexanecarboxylic acid (1/3) starting with(4-bromophenyl)acetic acid (4d), via tetrahydro-2H-pyran-2-yl2-(4-bromophenyl)acetate (5d). The crude product 1/9 was chromatographedon silica gel with petroleum ether-dioxane-acetic acid (85:15:2) andpetroleum ether-tert-butylmethyl ether-acetic acid (8:2:0.1) as eluentsto give 1-(4-bromophenyl)cyclohexanecarboxylic acid (1/9) in 25% yield.¹H NMR (CDCl₃, HMDSO) δ: 1.17-1.92 (8H, m); 2.28-2.59 (2H, m); 7.33 (2H,d, J=8.8 Hz); 7.47 (2H, d, J=8.8 Hz); 10.34 (1H, br s).

Example 28 Methyl 4-(2-methoxyethenyl)benzoate (7a)

To a suspension of methoxymethyltriphenylphosphonium chloride (6.366 g,18.5 mmol) in dry tetrahydrofuran (50 ml) under argon atmosphere at −78°C. slowly (ca. for 5 minutes) a 2.46 N solution of potassiumtert-butoxide in tetrahydrofuran (8.2 ml, 20.2 mmol) was added and thereaction mixture was stirred at this temperature for 1 hour. A solutionof methyl 4-formylbenzoate (6a) (2.531 g, 15.4 mmol) in tetrahydrofuran(10 ml) was added to the reaction mixture and the resultant suspensionwas stirred at −78° C. for 30 minutes. The cooling bath was removed andthe reaction mixture was stirred for 30 minutes allowing warming up toroom temperature. The mixture was partitioned between benzene (150 ml)and water (150 ml), and the organic layer was washed successively withwater (150 ml), brine (50 ml), and dried (Na₂SO₄). The solvent wasevaporated and the residue was chromatographed on silica gel (100 g)with toluene-triethylamine (100:0.25) as eluent to give the titlecompound (2.696 g, 91%) as a mixture of E and Z isomers (ca. 95:5).(E)-(7a): ¹H NMR (CDCl₃, HMDSO) δ: 3.67 (3H, s); 3.86 (3H, s); 5.81 (1H,d, J=13.5 Hz); 7.14 (1H, d, J=13.5 Hz); 7.25 (2H, d, J=8.5 Hz); 7.89(2H, d, J=8.5 Hz). A small additional singlet at 3.80 ppm and 2 doubletsat 5.23 (d, J=7.6 Hz); 6.22 ppm (d, J=7.6 Hz) in the ¹H NMR spectrum of7a was attributed to minor amounts (ca. 5%) of (Z)-(7a) isomer presentin the product.

Example 29 2-[4-(Methoxycarbonyl)phenyl]acetic acid (8a)

To a solution of methyl 4-(2-methoxyethenyl)benzoate (7a) (2.41 g, 12.5mmol) in dioxane (50 ml), 1N water solution of HCl (40 ml) was added andthe resultant mixture was stirred at room temperature for 12 hours. Thereaction mixture was extracted with ethyl acetate (3×50 ml), the organicextracts were combined, washed with brine (2×30 ml), and dried (Na₂SO₄).The solvents were evaporated and the residue was dissolved in acetone(70 ml), and cooled to −50° C. To the cold solution at this temperatureslowly (ca. for 5 minutes) 2.67 M Jones reagent (7.5 ml, 20.0 mmol) wasadded and the obtained mixture was stirred at −40 to −50° C. for 1 hourand at −30° C. for 20 minutes. Isopropyl alcohol (2 ml) was added to thereaction mixture and the cooling bath was removed allowing the reactionto warm up for 10 minutes. The mixture was poured into water (150) andextracted with ethyl acetate (3×100 ml). The organic layers werecombined, washed with brine (2×50), and dried (Na₂SO₄). The solvent wasevaporated and the residue was dissolved in a small amount of hotdioxane (1-2 ml). Addition of petroleum ether (4-6 ml) caused theformation of a precipitate. The mixture was filtered and the precipitatewas washed with dioxane-petroleum ether (1:4). The filtrate wasevaporated and the precipitate formation procedure was repeated asdescribed above. Then the filtrate was evaporated and the residue waschromatographed on silica gel (100 g) with petroleumether-dioxane-acetic acid (2.5:7.5:0.1) to give the title compound(0.681 g, 28%) as a white solid. ¹H NMR (CDCl₃, HMDSO) δ: 3.68 (2H, s);3.89 (3H, s); 7.33 (2H, d, J=8.2 Hz); 7.97 (2H, d, J=8.2 Hz); 10.82 (1H,br s).

Example 30 1-[4-(Methoxycarbonyl)phenyl]cyclohexanecarboxylic acid (1/4)

The title compound was obtained from 2-[4-(methoxycarbonyl)phenyl]aceticacid (8a) by the method described above for tetrahydro-2H-pyran-2-yl2-phenylacetate (5a) and 1-phenylcyclohexanecarboxylic acid (1/3). Thecrude product 1/4 was chromatographed on silica gel with toluene-ethylacetate-acetic acid (8:2:0.1) as eluent to give1-[4-(methoxycarbonyl)phenyl]-cyclohexanecarboxylic acid (1/4) in 68%yield (on 8a) as a white solid. ¹H NMR (CDCl₃, HMDSO) δ: 0.94-2.09 (8H,m); 2.25-2.65 (2H, m); 3.88 (3H, s); 7.49 (2H, d, J=8.6 Hz); 7.96 (2H,d, J=8.6 Hz); 10.07 (1H, br s).

Example 31 tert-Butyl 4-(2-methoxyethenyl)benzoate (7b)

The title compound was obtained from tert-butyl 4-formylbenzoate (6b)and methoxymethyltriphenylphosphonium chloride by a method analogous tothat described above for methyl 4-(2-methoxyethenyl)benzoate (7a), in94% yield as a mixture of E and Z isomers (ca. 3:2). (E)-(7b): ¹H NMR(CDCl₃, HMDSO) δ: 1.57 (9H, s); 3.70 (3H, s); 5.83 (1H, d, J=13.5 Hz);7.14(1H, d, J=13.5 Hz); 7.26 (2H, d, J=8.8 Hz); 7.87 (2H, d, J=8.8 Hz).(Z)-(7b): ¹H NMR (CDCl₃, HMDSO) δ: 1.57 (9H, s); 3.81 (3H, s); 5.26 (1H,d, J=7.5 Hz); 6.23(1H, d, J=7.5 Hz); 7.60 (2H, d, J=8.4 Hz); 7.89 (2H,d, J=8.4 Hz).

Example 32 2-[4-(tert-Butoxycarbonyl)phenyl]acetic acid (8b)

The title compound was obtained from tert-butyl4-(2-methoxyethenyl)benzoate (7b) by a method analogous to thatdescribed above for 2-[4-(methoxycarbonyl)phenyl)acetic acid (8a), in55% yield. ¹H NMR (CDCl₃, HMDSO) δ: 1.58 (9H, s); 3.69 (2H, s); 7.34(2H, d, J=8.2 Hz); 7.96 (2H, d, J=8.2 Hz); 10.12 (1H, br s).

Example 33 1-[4-(tert-Butoxycarbonyl)phenyl]cyclohexanecarboxylic acid(1/6)

The title compound was obtained from2-[4-(tert-butoxycarbonyl)phenyl]acetic acid (8b) by a method analogousto that described above for 1-[4-(methoxycarbonyl)phenyl]cyclohexanecarboxylic acid (1/4). The crude product 1/6 waschromatographed on silica gel with petroleum ether-dioxane-acetic acid(85:15:1) as eluent to give 1-[4-(tert-butoxycarbonyl)phenyl]-cyclohexanecarboxylic acid (1/6) in 27% yield. ¹H NMR (CDCl₃,HMDSO) δ: 1.16-1.99 (8H, m); 1.57 (9H, s); 2.22-2.61 (2H, m); 7.51 (2H,d, J=8.4 Hz); 7.96 (2H, d, J=8.4 Hz); 10.30 (1H, br s).

Example 34 1-(4-Hydroxyphenyl)cyclohexanecarboxylic acid (10)

The title compound was obtained from 2-[4-(hydroxy)phenyl)acetic acid(9) by the method analogous to that described for1-phenylcyclohexanecarboxylic acid (1/3). The crude product 10 waschromatographed on silica gel with toluene-ethyl acetate-acetic acid(9:1:0.1) as eluent to give 1-(4-hydroxyphenyl) cyclohexanecarboxylicacid (10). A thorough purification of the material was performed in anext step of the synthesis.

Example 35 1-[4-(Acetyloxy)phenyl]cyclohexanecarboxylic acid (1/7)

To a solution of 1-(4-hydroxyphenyl)cyclohexanecarboxylic acid (10)(1.264 g crude material, obtained from 1.000 g (6.57 mmol) of 9) inpyridine (5 ml) under argon atmosphere at 0° C. acetyl chloride (0.541g, 7.61 mmol) slowly (ca. over 10 minutes) was added and the mixture wasstirred for 15 minutes at this temperature. The ice bath was removed andthe reaction mixture was stirred at ambient temperature for 3 hours,then the content was poured into ice water (30 ml) and the pH of themedium was brought to 1-2 by adding conc.HCl. The mixture was extractedwith ethyl acetate (2×40 ml), the organic extract was washedsuccessively with water (30 ml), brine (15 ml), and dried (Na₂SO₄). Thesolvent was evaporated, the residue was dissolved in toluene andchromatographed on silica gel (100 g) with petroleumether-dioxane-acetic acid (8:2:0.1) as eluent affording the titlecompound (0.406 g, 23.5% based on 9) as a white solid. ¹H NMR (CDCl₃,HMDSO) δ: 1.06-1.98 (8H, m); 2.28 (3H, s); 2.30-2.63 (2H, m); 7.09 (2H,d, J=8.6 Hz); 7.46 (2H, d, J=8.6 Hz); 10.49 (1H, br s).

Example 36 Methyl 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoate (11)

To a stirred solution of1-[4-(methoxycarbonyl)phenyl]cyclohexanecarboxylic acid (1/4) (0.413 g,1.57 mmol) in refluxing benzene (5 ml), N,N-dimethylformamidedi-tert-butyl acetal (1.5 ml, 6.25 mmol) was added over 15 minutes. Thereaction mixture was refluxed for 3 hours, then allowed to cool anddiluted with benzene (50 ml). The obtained solution was washedsuccessively with water (25 ml), brine (15 ml), and dried (Na₂SO₄). Thesolvent was evaporated and the residue was chromatographed on silica gel(30 g) with toluene as eluent to give the title compound (0.273 g, 54%).¹H NMR (CDCl₃, HMDSO) δ: 1.04-2.09 (8H, m); 1.34 (9H, s); 2.22-2.60 (2H,m); 3.89 (3H, s); 7.48 (2H, d, J=8.4 Hz); 7.99 (2H, d, J=8.4 Hz).

Example 37 4-[1-(tert-Butoxycarbonyl)cyclohexyl]benzoic acid (12)

To a solution of methyl 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoate(1) (0.273 g, 0.86 mmol) in tetrahydrofuran (5 ml) was added 0.63 N LiOHwater solution (3 ml, 1.89 mmol) and the resultant suspension wasstirred at ambient temperature for 5 days. The reaction mixture wasdiluted with water (20 ml) and saturated NaH₂PO₄ (5 ml), and theobtained suspension was extracted with ethyl acetate (2×30 ml). Theextract was washed with brine (15 ml), dried (Na₂SO₄), and the solventwas removed in vacuo. The residue was chromatographed on silica gel withtoluene-ethyl acetate-acetic acid (8:2:01) as eluent to give the titlecompound (0.231 g, 88%) as a white solid. ¹H NMR (CDCl₃, HMDSO) δ:1.07-1.91 (8H, m); 1.35 (9H, s); 2.20-2.63 (2H, m); 7.52 (2H, d, J=8.5Hz); 8.06 (2H, d, J=8.5 Hz); 11.20 (1H, br s).

Example 38 Isopropyl 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoate (13)

To a solution of 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoic acid (12)(0.219 g, 0.72 mmol) in dichloromethane (5 ml) under argon atmosphere atice bath temperature oxalyl chloride (0.3 ml, 3.44 mmol) and a drop ofdimethylformamide were added. The reaction mixture was stirred atambient temperature for 15 minutes and at 40° C. for 1 hour, then thevolatiles were evaporated and the residue was dried in vacuo. Theresidue (0.247 g) was dissolved in tetrahydrofuran (4 ml) and4-dimethylaminopyridine (0.176 g, 1.43 mmol) and isopropanol (0.35 ml,4.57 mmol) were added to the resulting solution. The mixture was stirredovernight, supplemented with benzene (50 ml), successively washed withwater (30 ml), brine (20 ml), and dried (Na₂SO₄). The solvents wereevaporated and the residue was chromatographed on silica gel withtoluene-ethyl acetate (97:3) as eluent to give the title compound (0.226g, 91%) as an oil. ¹H NMR (CDCl₃, HMDSO) δ: 1.01-1.87 (8H, m); 1.34 (6H,d, J=6.5 Hz); 1.34 (9H, s); 2.17-2.61 (2H, m); 5.23 (1H, sept, J=6.5Hz); 7.46 (2H, d, J=8.8 Hz); 7.98 (2H, d, J=8.8 Hz).

Example 39 1-[4-(Isopropoxycarbonyl)phenyl]cyclohexanecarboxylic acid(1/10)

To a solution of isopropyl 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoate(13) (0.136 g, 0.39 mmol) in dichloromethane (1.5 ml) was addedtrifluoroacetic acid (0.5 ml) and the mixture was stirred at ambienttemperature under argon atmosphere for 2.5 hours. The volatiles wereevaporated and the residue was chromatographed on silica gel withtoluene-dioxane-acetic acid (95:5:1) as eluent to give the titlecompound (0.105 g, 92%).

¹H NMR (CDCl₃, HMDSO) δ: 1.04-2.03 (8H, m); 1.33 (6H, d, J=6.5 Hz);2.26-2.63 (2H, m); 5.24 (1H, sept, J=6.5 Hz); 7.51 (2H, d, J=8.7 Hz);8.01 (2H, d, J=8.7 Hz); 10.34 (1H, br s).

Example 40 N-(Benzyloxy)-4-hydroxybenzamide (14)

To a mixture of 4-hydroxybenzoic acid (16) (0.424 g, 3.07 mmol),O-benzylhydroxylamine hydrochloride (0.490 g, 3.07 mmol), and4-dimethylaminopyridine (0.414 g, 3.39 mmol) in dichloromethane (30 ml)under argon atmosphere 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.643 g, 3.35 mmol) was added and the resultant mixturewas stirred at room temperature for 5 hours. The reaction mixture waspoured into a mixture of saturated NaH₂PO₄ (30 ml) and water (70 ml),and extracted with ethyl acetate (2×75 ml). The extract was washed witha mixture of saturated NaH₂PO₄ (15 ml) and water (35 ml), brine (50 ml),and dried (MgSO₄). The solvent was evaporated and the residue waschromatographed on silica gel (50 g) with benzene-ethyl acetate-aceticacid (75:25:1, 100 ml) and benzene-ethyl acetate-acetic acid (50:50:1,300 ml) as eluents to give the title compound (0.338 g, 45%) as a whitesolid. ¹H NMR (DMSO-d₆, HMDSO), δ: 4.88 (2H, s); 6.79 (2H, d, J=8.8 Hz);7.23-7.55 (5H, m); 7.59 (2H, d, J=8.8 Hz); 10.02 (1H, br s); 11.48 (1H,s).

Example 41 4-(Acetyloxy)benzoic acid (17)

To a mixture of 4-hydroxybenzoic acid (16) (20.0 g, 144.8 mmol) andpyridine (60 ml, 742 mmol) at 0° C. was added acetyl chloride (12 ml,169 mol) over 5 minutes. The resulting mixture was stirred at ice bathtemperature for 30 minutes and for 1 hour at room temperature. Themixture was poured into ice water (500 ml) and the pH of the medium wasbrought to 1-2 by adding conc. HCl (ca. 40 ml). The precipitate wasfiltered, washed with water (100 ml), and dried (Na₂SO₄). The obtainedsolid material was crystallized from methanol-water (1:1) (200 ml)affording the title compound (21.485 g, 82.3%) as white crystals, m.p.181-183° C. ¹H NMR (CDCl₃, HMDSO) δ: 2.32 (3H, s); 7.22 (2H, d, J=8.2Hz); 8.16 (2H, d, J=8.2 Hz); 10.50 (1H, brs).

Example 42 4-{[(Benzyloxy)amino]carbonyl}phenyl acetate (18)

To a suspension of 4-(acetyloxy)benzoic acid (17) (10.0 g, 55.5 mmol) indichloromethane (200 ml) oxalyl chloride (15 ml, 172 mmol) anddimethylformamide (0.1 ml) were added. The reaction mixture was stirredat ambient temperature for 30 minutes and at reflux temperature for 1hour. The volatiles were evaporated in vacuo, the residue was dissolvedin benzene (100 ml) and the solvent was evaporated again. The procedurewas repeated several times until the poignant smell disappeared afterdrying in vacuo. The viscous oil was dissolved in tetrahydrofuran (100ml) and this solution slowly over 10 minutes was added to a prearrangedmixture consisting of saturated NaHCO₃ solution (100 ml), solid NaHCO₃(11 g), O-benzylhydroxylamine hydrochloride (9.90 g, 62 mmol), andtetrahydrofuran (150 ml). The resulting mixture was stirred at ambienttemperature for 1 hour and the volume of the reaction mixture wasdecreased ca. twice by evaporating the mixture on vacuum rotaryevaporator. The residue was extracted with ethyl acetate (3×100 ml), thecombined organic extracts were successively washed with 2N HCl (100 ml),water (100 ml), brine (100 ml), and dried (Na₂SO₄). The solvents wereevaporated and the residue was crystallized from toluene to give thetitle compound (14.275 g, 90%) as white crystals, m.p. 120-122° C. ¹HNMR (CDCl₃, HMDSO) δ: 2.30 (3H, s); 5.02 (2H, s); 7.14 (2H, d, J=8.6Hz); 7.26-7.54 (5H, m); 7.69 (2H, d, J=8.6 Hz); 8.56 (1H, br s).

Example 43 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl acetate (19)

To a solution of 4-{[(benzyloxy)amino]carbonyl}phenyl acetate (18)(2.000 g, 7.0 mmol) and benzyl bromide (3.59 g, 21.0 mmol) inhexamethylphosphoric triamide (10 ml) Cs₂CO₃ (2.51 g, 7.7 mmol) wasadded and the reaction mixture was stirred at ambient temperature for 24hours. The mixture was diluted with benzene (50 ml) and washedsuccessively with water (2×30 ml), 2N HCl (30 ml), water (2×30 ml),brine (30 ml), and dried (Na₂SO₄). The solvent was evaporated and theresidue was chromatographed on silica gel (100 g) with petroleumether-benzene (1:1) and benzene-ethyl acetate (9:1) as eluents to give4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl acetate (19) (1.743 g,66%) as an oil, R_(f) 0.83 (toluene-ethyl acetate, 9:1), and4-{[benzyl(benzyloxy)amino]-carbonyl}phenyl acetate (20) (0.744 g, 28%)as a white solid, R_(f) 0.48 (toluene-ethyl acetate, 9:1). (19): ¹H NMR(DMSO-d₆, HMDSO) δ: 2.24 (3H, s); 5.12 (2H, s); 5.32 (2H, s); 7.17 (2H,d, J=8.7 Hz); 7.25-7.54 (10H, m); 7.66 (2H, d, J=8.7 Hz). GC-MS, m/z(%): 375 (0.2), 268 (0.3), 253 (1), 227 (0.6), 211 (1.3), 196 (0.5), 180(2.3), 163 (19.5), 121 (36), 107 (5.2), 91 (100), 77 (6), 65 (16). IR(film, cm⁻¹): 1758, 1616, 1578, 1507. (20): ¹H NMR (DMSO-d₆, HMDSO) δ:2.28 (3H, s); 4.72 (2H, s); 4.99 (2H, s); 6.88-7.10 (2H, m); 7.12-7.50(8H, m); 7.22 (2H, d, J=8.0 Hz); 7.63 (2H, d, J=8.0 Hz). GC-MS, m/z(%):269 (36), 227 (27), 121 (100), 106 (25), 91 (46), 77 (14), 65 (26).IR (nujol, cm⁻¹): 1756, 1663, 1604, 1578, 1507.

Example 44 Benzyl N-(benzyloxy)-4-hydroxybenzenecarboximidoate (15)

To a solution of 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl acetate(19) (1.671 g, 4.45 mmol) in dry methanol (30 ml) 3.43 N sodiummethoxide solution in methanol (1.3 ml, 4.46 mmol) was added and thereaction mixture was stirred at ambient temperature until the startingmaterial disappeared (ca. 1 hour). The mixture was poured into a mixtureof water (60 ml) and saturated NaH₂PO₄ (30 ml), and extracted with ethylacetate (2×25 ml). The extract was washed with brine (30 ml) and dried(Na₂SO₄). The solvent was evaporated and the residue was chromatographedon silicagel (50 g) with benzene-ethyl acetate (9:1) as eluent to givebenzyl N-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) (1.428 g, 96%)as an interchangeable mixture (2D TLC) of 2 isomers with R_(f) 0.62 andR_(f) 0.49 (toluene-ethyl acetate, 9:1). Major (less polar) isomer of15: ¹H NMR (DMSO-d₆, HMDSO) δ: 4.99 (2H, s); 5.09 (2H, s); 6.80 (2H, d,J=8.7 Hz); 7.27-7.53 (10H, m); 7.67 (2H, d, J=8.7 Hz); 9.96 (1H, s).Minor (more polar) isomer of 15: ¹H NMR (DMSO-d₆, HMDSO) δ: 5.06 (2H,s); 5.24 (2H, s); 6.75 (2H, d, J=8.6 Hz); 7.27-7.53 (10H, m); 7.67 (2H,d, J=8.6 Hz); 9.84 (1H, s).

Example 45 1-(4-Methoxyphenyl)cyclohexanecarbonyl chloride (21a)

To a solution of 1-(4-methoxyphenyl)-cyclohexanecarboxylic acid (1/1)(0.075 g, 0.32 mmol) in dry dichloromethane (2 ml) under argonatmosphere at ice bath temperature oxalyl chloride (0.327 g, 2.57 mmol)and one drop of dimethylformamide were added. The reaction mixture wasstirred at room temperature for 15 minutes and at 40° C. for 1 hour,then concentrated under reduced pressure to give crude title compound(0.082 g, ca. 100%). The crude product was immediately utilized in thenext step of the synthesis without further purification.

Example 46 1-Phenylcyclohexanecarbonyl chloride (21b)

The title compound was obtained from 1-phenylcyclohexanecarboxylic acid(1/1) by a method analogous to that of the previous example, in ca. 100%yield. The crude product was immediately utilized in the next step ofthe synthesis without further purification.

Example 47 Methyl 4-[1-(chlorocarbonyl)cyclohexyl]benzoate (21c)

The title compound was obtained from1-[4-(methoxycarbonyl)phenyl]-cyclohexanecarboxylic acid (1/4) by amethod analogous to that of the previous example, in ca. 100% yield. Thecrude product was immediately utilized in the next step of the synthesiswithout further purification.

Example 48 1-(2-Chloro-6-fluorophenyl)cyclohexanecarbonyl chloride (21d)

The title compound was obtained from1-(2-chloro-6-fluorophenyl)cyclohexanecarboxylic acid (1/11) by a methodanalogous to that of the previous example, in ca. 100% yield. The crudeproduct was immediately utilized in the next step of the synthesiswithout further purification.

Example 49 4-{[(Benzyloxy)amino]carbonyl}phenyl1-(4-methoxyphenyl)cyclohexanecarboxylate (22a)

To a solution of N-(benzyloxy)₄-hydroxybenzamide (14) (0.078 g, 0.32mmol) and 4-dimethylaminopyridine (0.047 g, 0.38 mmol) intetrahydrofuran (2 ml) under argon atmosphere at ice bath temperature asolution of 1-(4-methoxyphenyl) cyclohexanecarbonyl chloride (21a)(0.082 g, obtained in the preceding step of the synthesis) intetrahydrofuran (2 ml) was added. The resultant white suspension wasstirred at room temperature overnight and poured into ethyl acetate (80ml). The ethyl acetate extract was washed with water (50 ml), brine (30ml), and dried (Na₂SO₄). The solvent was evaporated and the residue wasdissolved in a small amount of benzene (0.5-1 ml). The precipitatedsolid was filtered off, the filtrate was evaporated and chromatographedon silicagel (10 g) with benzene-ethyl acetate (9:1) as eluent affordingthe title compound (0.077 g, 52% based on 1/1) as a white solid. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.07-2.01 (8H, m); 2.21-2.61 (2H, m, overlapped witha signal of DMSO); 3.75 (3H, s); 4.92 (2H, s); 6.97 (2H, d, J=8.5 Hz);7.04 (2H, d, J=8.2 Hz); 7.23-7.54 (7H, m); 7.76 (2H, d, J=8.5 Hz); 11.77(1H, s).

Example 50 4-{[(Benzyloxy)amino]carbonyl}phenyl1-phenylcyclohexanecarboxylate (22b)

The title compound was obtained from N-(benzyloxy)-4-hydroxybenzamide(14) and 1-phenylcyclohexanecarbonyl chloride (21b) by a methodanalogous to that of the previous example, in 32% yield (on 14) as awhite solid. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.05-2.01 (8H, m); 2.23-2.61(2H, m, overlapped with a signal of DMSO); 4.92 (2H, s); 7.06 (2H, d,J=8.6 Hz); 7.25-7.59 (10H, m); 7.77 (2H, m); 11.78 (1H, s).

Example 51 Methyl4-{1-[(4-{[(benzyloxy)amino]carbonyl}phenoxy)carbonyl]cyclohexyl}benzoate(22c)

The title compound was obtained from N-(benzyloxy)-4-hydroxybenzamide(14) and methyl 4-[1-(chlorocarbonyl)cyclohexyl]benzoate (21c) by amethod analogous to that of the previous example, in 22% yield (on 14)as a white solid. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.05-2.03 (8H, m);2.25-2.69 (2H, m, overlapped with a signal of DMSO); 3.85 (3H, s); 4.92(2H, s); 7.07 (2H, d, J=8.6 Hz); 7.29-7.52 (5H, m); 7.65 (2H, d, J=8.3Hz); 7.77 (2H, d, J=8.6 Hz); 8.02 (2H, d, J=8.3 Hz); 11.79 (1H, br s).

Example 52 4-{[(Benzyloxy)amino]carbonyl}phenyl1-(2-chloro-6-fluorophenyl)cyclohexanecarboxylate (22d)

The title compound was obtained from N-(benzyloxy)-4-hydroxybenzamide(14) and 1-(2-chloro-6-fluorophenyl)cyclohexanecarbonyl chloride (21d)by a method analogous to that of the previous example, in 44% yield (on14). ¹H NMR (CDCl₃, HMDSO) δ: 1.17-2.02 (6H, m); 2.20-2.60 (4H, m); 4.99(2H, s); 6.83-7.78 (3H, m); 7.07 (2H, d, J=8.4 Hz); 7.37 (5H, s); 7.63(2H, d, J=8.4 Hz); 8.38 (1H, br s).

Example 53 4-[(Hydroxyamino)carbonyl]phenyl1-(4-methoxyphenyl)-cyclohexanecarboxylate (PX118478)

A mixture of 4-{[(benzyloxy)amino]carbonyl]phenyl 1-(4-methoxyphenyl)cyclohexanecarboxylate (22a) (0.072 g, 0.16 mmol) and 5% palladium onactivated carbon (0.054 g) in methanol (1 ml) was hydrogenated at roomtemperature until the starting material disappeared (ca. 45 minutes).The black suspension was filtered, the catalyst was washed with methanol(3×1 ml), and the filtrate was evaporated to give a white solid. Thesolid was suspended in diethyl ether (3 ml) and the mixture wasintensively stirred overnight. The solid was filtered, washed withdiethyl ether (1 ml), and dried in vacuum to give the title compound(0.037 g, 64%) as white crystals, m.p. 127-129° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 1.18-1.90 (8H, m); 2.36-2.65 (2H, m, overlapped with a signalof DMSO); 3.76 (3H, s); 6.97 (2H, d, J=8.6 Hz); 7.01 (2H, d, J=8.8 Hz);7.40 (2H, d, J=8.8 Hz); 7.77 (2H, d, J=8.6 Hz); 9.07 (1H, br s); 11.23(1H, br s). HPLC analysis on Symmetry C₈ column: impurities 2.2% (columnsize 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH2.5), 60:40; detector UV 230 nm; sample concentration 0.3 mg/ml; flowrate 1.0 ml/min). Anal. Calcd for C₂₁H₂₃NO₅*0.3H₂O, %: C, 67.29; H,6.35,; N, 3.74. Found, %: C, 67.29; H, 6.23; N, 3.76.

Example 54 4-[(Hydroxyamino)carbonyl]phenyl1-phenylcyclohexanecarboxylate (PX118479)

The title compound was obtained from4-{[(benzyloxy)amino]carbonyl}phenyl 1-phenylcyclohexanecarboxylate(22b) by a method analogous to that of the previous example, in 89%yield as white crystals, m.p. 142-144° C. ¹H NMR (DMSO-d₆, HMDSO) δ:1.16-1.94 (8H, m); 2.35-2.64 (2H, m, overlapped with a signal of DMSO);7.02 (2H, d, J=8.7 Hz); 7.26-7.54 (5H, m); 7.77 (2H, d, J=8.7 Hz); 9.06(1H, s); 11.24 (1H, br s). HPLC analysis on Symmetry C₈ column:impurities 2% (column size 3.9×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 50:50; detector UV 230 nm; sampleconcentration 0.5 mg/ml; flow rate 1.1 ml/min). Anal. Calcd forC₂₀H₂₁NO₄*0.4H₂O, %: C, 69.31; H, 6.34; N, 4.04. Found, %: C, 69.36; H,6.24; N, 3.97.

Example 55 Methyl 4-[1-({4-[(hydroxyamino)carbonyl]phenoxy}carbonyl)-cyclohexyl]benzoate (PX118480)

The title compound was obtained from methyl4-{1-[(4-{[(benzyloxy)amino]carbonyl}phenoxy)carbonyl]cyclohexyl)-benzoate (22c) by a method analogous tothat of the previous example, in 64% yield as white crystals, m.p.129-131° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.13-1.99 (8H, m); 2.35-2.58 (2H,m, overlapped with a signal of DMSO); 3.86 (3H, s); 7.05 (2H, d, J=8.6Hz); 7.65 (2H, d, J=8.4 Hz); 7.77 (2H, d, J=8.6 Hz); 8.01 (2H, d, J=8.4Hz); 9.07 (1H, s); 11.25 (1H, s). HPLC analysis on Symmetry C₈ column:impurities 2.5% (column size 3.9×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 60:40; detector UV 254 nm; sampleconcentration 0.5 mg/ml; flow rate 1.0 ml/min). Anal. Calcd forC₂₂H₂₃NO₆*0.35H₂O, %: C, 65.45; H, 5.92; N, 3.47. Found, %: C, 65.17; H,5.76; N, 3.49.

Example 56 4-[(Hydroxyamino)carbonyl]phenyl 1-(2-chloro-6-fluorophenyl)-cyclohexanecarboxylate (PX119101)

The title compound was obtained from methyl4-{[(benzyloxy)amino]carbonyl}phenyl1-(2-chloro-6-fluorophenyl)cyclohexanecarboxylate (22d) by a methodanalogous to that of the previous example. The crude product afterfiltration and evaporation of methanol was chromatographed on silica gelwith chloroform-methanol (95:5) as eluent and crystallized fromdichloromethane-petroleum ether (1:3) at −18° C. to give the compoundPX119101 in 45% yield, m.p. 101-102° C. ¹H NMR (DMSO-d₆, HMDSO) δ:1.10-1.92 (6H, m); 2.27-2.60 (4H, m, overlapped with a signal of DMSO);7.13 (2H, d, J=8.4 Hz); 7.07-7.80 (3H, m); 7.80 (2H, d, J=8.4 Hz); 9.08(1H, s); 11.26 (1H, s). HPLC analysis on Omnispher C₁₈ column:impurities 1% (column size 4.6×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 60:40; detector UV 210 nm; sampleconcentration 1.0 mg/ml; flow rate 1.0 ml/min). Anal. Calcd forC₂₀H₁₉ClFNO₄, %: C, 61.31; H, 4.89; N, 3.57. Found, %: C, 61.22; H,4.86; N, 3.41.

Example 57 1-(4-Ethoxyphenyl)cyclohexanecarbonyl chloride (23a)

The title compound was obtained from1-(4-ethoxyphenyl)cyclohexanecarboxylic acid (1/5) by a method analogousto that described for 1-(4-methoxyphenyl)cyclohexanecarbonyl chloride(21a), in ca. 100% yield. The crude product was immediately utilized inthe next step of the synthesis without further purification.

Example 58 tert-Butyl 4-[1-(chlorocarbonyl)cyclohexyl]benzoate (23b)

The title compound was obtained from 1-[4-(tert-butoxycarbonyl)phenyl]cyclohexanecarboxylic acid (1/2) by a method analogous to that describedfor the previous example, in ca. 100% yield. The crude product wasimmediately utilized in the next step of the synthesis without furtherpurification.

Example 59 1-(4-Acetoxyphenyl)cyclohexanecarbonyl chloride (23c)

The title compound was obtained from1-(4-acetoxyphenyl)cyclohexanecarboxylic acid (1/7) by a methodanalogous to that described the previous example, in ca. 100% yield. Thecrude product was immediately utilized in the next step of the synthesiswithout further purification.

Example 60 1-(4-Methylphenyl)cyclohexanecarbonyl chloride (23d)

The title compound was obtained from1-(4-methylphenyl)cyclohexanecarboxylic acid (1/13) by a methodanalogous to that described for the previous example, in ca. 100% yield.The crude product was immediately utilized in the next step of thesynthesis without further purification.

Example 61 1-[1,1′-Biphenyl]-4-ylcyclohexanecarbonyl chloride (23e)

The title compound was obtained from1-[1,1′-biphenyl]-4-ylcyclohexanecarboxylic acid (1/14) by a methodanalogous to that described for the previous example, in ca. 100% yield.The crude product was immediately utilized in the next step of thesynthesis without further purification.

Example 62 1-(4-Chlorophenyl)cyclohexanecarbonyl chloride (23f)

The title compound was obtained from1-(4-chlorophenyl)cyclohexanecarboxylic acid (1/15) by a methodanalogous to that described for the previous example, in ca. 100% yield.The crude product was immediately utilized in the next step of thesynthesis without further purification.

Example 63 1-(3-Fluorophenyl)cyclohexanecarbonyl chloride (23g)

The title compound was obtained from1-(3-fluorophenyl)cyclohexanecarboxylic acid (1/16) by a methodanalogous to that described for the previous example, in ca. 100% yield.The crude product was immediately utilized in the next step of thesynthesis without further purification.

Example 64 1-(2-Fluorophenyl)cyclohexanecarbonyl chloride (23h)

The title compound was obtained from1-(2-fluorophenyl)cyclohexanecarboxylic acid (1/17) by a methodanalogous to that described the previous example, in ca. 100% yield. Thecrude product was immediately utilized in the next step of the synthesiswithout further purification.

Example 65 1-(2-Chloro-4-fluorophenyl)cyclohexanecarbonyl chloride (23i)

The title compound was obtained from1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid (1/18) by a methodanalogous to that described the previous example, in ca. 100% yield. Thecrude product was immediately utilized in the next step of the synthesiswithout further purification.

Example 66 1-(4-Fluorophenyl)cyclohexanecarbonyl chloride (23j)

The title compound was obtained from1-(4-fluorophenyl)cyclohexanecarboxylic acid (1/19) by a methodanalogous to that described for the previous example, in ca. 100% yield.The crude product was immediately utilized in the next step of thesynthesis without further purification.

Example 67 1-(4-Bromophenyl)cyclohexanecarbonyl chloride (23k)

The title compound was obtained from1-(4-bromophenyl)cyclohexanecarboxylic acid (1/9) by a method analogousto that described for the previous example, in ca. 100% yield. The crudeproduct was immediately utilized in the next step of the synthesiswithout further purification.

Example 68 Isopropyl 4-[1-(chlorocarbonyl)cyclohexyl]benzoate (231)

The title compound was obtained from 1-[4-(isopropoxycarbonyl)phenyl]cyclohexanecarboxylic acid (1/10) by a method analogous to thatdescribed for the previous example, in ca. 100% yield. The crude productwas immediately utilized in the next step of the synthesis withoutfurther purification.

Example 69 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-ethoxyphenyl)cyclohexanecarboxylate (24a)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(4-ethoxyphenyl)cyclohexanecarbonyl chloride (23a) by a methodanalogous to that described for 4-([(Benzyloxy)amino]carbonyl}phenyl1-(4-methoxyphenyl)cyclohexanecarboxylate (22a), in 68% yield (on 1/5)in a form of 2 individual (slow equilibrium of interchange) isomers(87:13). Major (less polar) isomer of 24a: ¹H NMR (CDCl₃, HMDSO) δ:1.17-1.92 (8H, m); 1.39 (3H, t, J=7.0 Hz); 2.05-2.77 (2H, m); 4.03 (2H,q, J=7.0 Hz); 5.01 (2H, s); 5.12 (2H, s); 6.92 (2H, d, J=8.8 Hz); 6.94(2H, d, J=8.8 Hz); 7.32 (10H, s); 7.42 (2H, d, J=8.8 Hz); 7.84 (2H, d,J=8.8 Hz). Minor (more polar) isomer of 24a: ¹H NMR (CDCl₃, HMDSO) δ:1.10-1.91 (8H, m); 1.39 (3H, t, J=7.0 Hz); 2.10-2.73 (2H, m); 4.03 (2H,q, J=7.0 Hz); 5.12 (2H, s); 5.30 (2H, s); 6.89 (2H, d, J=8.8 Hz); 6.91(2H, d, J=8.8 Hz); 7.32-7.51 (12H, m); 7.63 (2H, d, J=8.8H

Example 70 tert-Butyl4-{1-[(4-{(benzyloxy)[(benzyloxy)imino]methyl}phenoxy)carbonyl]cyclohexyl}benzoate(24b)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and tert-butyl4-[1-(chlorocarbonyl) cyclohexyl]benzoate (23b) by a method analogous tothat described for the previous example, in 76% yield (on 1/12). ¹H NMR(CDCl₃, HMDSO) δ: 1.15-1.92 (8H, m); 1.57 (9H, s); 2.25-2.77 (2H, m);5.00 (2H, s); 5.12 (2H, s); 6.93 (2H, d, J=8.2 Hz); 7.21-7.47 (10H, m);7.56 (2H, d, J=8.5 Hz); 7.80 (2H, d, J=8.2 Hz); 8.00 (2H, d, J=8.5 Hz).

Example 71 4-{(Benzyloxy)[(benzyloxy)imino]methyl]phenyl1-[4-(acetyloxy)phenyl]cyclohexanecarboxylate (24c)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(4-acetoxyphenyl)cyclohexanecarbonyl chloride (23c) by a methodanalogous to that described for the previous example, in 95% (on 1/7).¹H NMR (CDCl₃, HMDSO) δ: 1.21-1.88 (8H, m); 2.23 (3H, s); 2.32-2.68 (2H,m); 4.88 (2H, s); 5.00 (2H, s); 6.78 (2H, d, J=8.8 Hz); 6.94 (2H, d,J=8.8 Hz); 7.01-7.28 (10H, m); 7.32 (2H, d, J=8.8 Hz); 7.66 (2H, d,J=8.8 Hz).

Example 72 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-methylphenyl)cyclohexanecarboxylate (24d)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(4-methylphenyl)cyclohexanecarbonyl chloride (23d) by a methodanalogous to that described for the previous example, in 51% (on 1113)as a mixture of 2 isomers (76:24). Major (less polar) isomer of 24d: ¹HNMR (CDCl₃, HMDSO) δ: 1.19-2.01 (8H, m); 2.12-2.74 (2H, m); 2.30 (3H,s); 4.97 (2H, s); 5.10 (2H, s); 6.93 (2H, d, J=8.8 Hz); 7.03-7.56 (14H,m); 7.82 (2H, d, J=8.8 Hz). Minor (more polar) isomer of 24d: ¹H NMR(CDCl₃, HMDSO) δ: 1.18-2.08 (8H, m); 2.17-2.79 (2H, m); 2.32 (3H, s);5.11 (2H, s); 5.28 (2H, s); 6.88 (2H, d, J=9.0 Hz); 7.04-7.56 (14H, m);7.64 (2H, d, J=9.0 Hz).

Example 73 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-[1,1′-biphenyl]-4-ylcyclohexanecarboxylate (24e)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-[1,1′-biphenyl]-4-ylcyclohexanecarbonyl chloride (23e) by a methodanalogous to that described for the previous example, in 73% yield (on1/14). ¹H NMR (CDCl₃, HMDSO) δ: 1.06-2.10 (8H, m); 2.41-2.88 (2H, m);4.99 (2H, s); 5.11 (2H, s); 6.96 (2H, d, J=8.8 Hz); 7.14-7.74 (19H, m);7.79 (2H, d, J=8.8 Hz).

Example 74 4-[(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-chorophenyl)cyclohexanecarboxylate (24f)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(4-chlorophenyl)cyclohexanecarbonyl chloride (23f) by a methodanalogous to that described for the previous example, in 70% yield (on1/15) as a mixture of 2 isomers (92:8). Major isomer of 24f: ¹H NMR(CDCl₃, HMDSO) δ: 1.14-1.98 (8H, m); 2.31-2.78 (2H, m); 4.99 (2H, s);5.11 (2H, s); 6.90 (2H, d, J=8.8 Hz); 7.09-7.53 (14H, m); 7.80 (2H, d,J=8.8 Hz).

Example 75 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(3-fluorophenyl)cyclohexanecarboxylate (24g)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(3-fluorophenyl)cyclohexanecarbonyl chloride (23g) by a methodanalogous to that described for the previous example, in 66% yield (on1/16) as a mixture of 2 isomers (93:7). Major isomer of 24g: ¹H NMR(CDCl₃, HMDSO) δ: 1.08-1.97 (8H, m); 2.30-2.78 (2H, m); 5.00 (2H, s);5.12 (2H, s); 6.79-7.52(14H, m); 6.94 (2H, d, J=8.8 Hz); 7.83 (2H, d,J=8.8 Hz).

Example 76 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(2-fluorophenyl)cyclohexanecarboxylate (24h)

The title compound was obtained from benzylN-(benzyloxy)₄-hydroxybenzenecarboximidoate (15) and1-(2-fluorophenyl)cyclohexanecarbonyl chloride (23h) by a methodanalogous to that described for the previous example, in 66% yield (on1/17) as a mixture of 2 isomers (98:2). Major isomer of 24h: ¹H NMR(CDCl₃, HMDSO) δ: 1.10-2.12 (8H, m); 2.25-2.67 (2H, m); 4.99 (2H, s);5.11 (2H, s); 6.90-7.61 (14H, m); 7.00 (2H, d, J=8.8 Hz); 7.82 (2H, d,J=8.8 Hz).

Example 77 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylate (24i)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(2-chloro-4-fluorophenyl)cyclohexanecarbonyl chloride (23i) by amethod analogous to that described for the previous example, in 85%yield (on 1/18) as a mixture of 2 isomers (98:2). Major isomer of 24j:¹H NMR (CDCl₃, HMDSO) δ: 1.10-2.18 (8H, m); 2.18-2.71 (2H, m); 5.00 (2H,s); 5.12 (2H, s); 6.74-7.63 (13H, m); 7.00 (2H, d, J=8.8 Hz); 7.82 (2H,d, J=8.8 Hz).

Example 78 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-fluorophenyl-)cyclohexanecarboxylate (24j)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(4-fluorophenyl)cyclohexanecarbonyl chloride (23j) by a methodanalogous to that described for the previous example, in 90% yield (on1/19) as a mixture of 2 isomers (98:2). Major isomer of 24j: ¹H NMR(CDCl₃, HMDSO) δ: 1.05-1.95 (8H, m); 2.31-2.77 (2H, m); 4.99 (2H, s);5.11 (2H, s); 6.70-7.58 (14H, m); 6.89 (2H, d, J=8.8 Hz); 7.81 (2H, d,J=8.8 Hz).

Example 79 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-bromophenyl)cyclohexanecarboxylate (24k)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(4-bromophenyl)cyclohexanecarbonyl chloride (23k) by a methodanalogous to that described for the previous example, in 90% yield (on1/9) as a mixture of 2 isomers (81:19). Major (less polar) isomer of24k: ¹H NMR (CDCl₃, HMDSO) δ: 1.17-1.97 (8H, m); 2.39-2.73 (2H, m); 5.01(2H, s); 5.12 (2H, s); 6.92 (2H, d, J=8.5 Hz); 7.26-7.50 (10H, m); 7.36(2H, d, J=8.8 Hz); 7.48 (2H, d, J=8.8 Hz); 7.82 (2H, d, J=8.5 Hz). Minor(more polar) isomer of 24k: ¹H NMR (CDCl₃, HMDSO) δ: 1.12-1.92 (8H, m);2.28-2.65 (2H, m); 5.12 (2H, s); 5.29 (2H, s); 6.86 (2H, d, J=8.5 Hz);7.14-7.42 (12H, m); 7.49 (2H, d, J=8.8 Hz); 7.62 (2H, d, J=8.5 Hz)

Example 80 Isopropyl4-{1-[(4-{(benzyloxy)[(benzyloxy)imino]methyl}phenoxy)carbonyl]cyclohexyl}benzoate(24l)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and isopropyl4-[1-(chlorocarbonyl)cyclohexyl]benzoate (231) by a method analogous tothat described for the previous example, in 94% yield (on 1/10) as amixture of 2 isomers (96:4). Major (less polar) isomer of 24l: ¹H NMR(CDCl₃, HMDSO) δ: 1.14-1.93 (8H, m); 1.34 (6H, d, J=6.5 Hz); 2.39-2.79(2H, m); 5.00 (2H, s); 5.12 (2H, s); 5.25 (1H, sept, J=6.5 Hz); 6.91(2H, d, J=8.0 Hz); 7.31 (5H, s); 7.34 (5H, m); 7.55 (2H, d, J=8.4 Hz);7.81 (2H, d, J=8.0 Hz); 8.03 (2H, d, J=8.4 Hz). Minor (more polar)isomer of 24l: ¹H NMR (CDCl₃, HMDSO) δ: 1.03-2.13 (8H, m); 1.34 (6H, d,J=6.0 Hz); 2.33-2.80 (2H, m); 4.94-5.40 (1H, m); 5.12 (2H, s); 5.30 (2H,s); 6.85 (2H, d, J=8.2 Hz); 7.21-7.47 (10H, m); 7.55 (2H, d, J=8.5 Hz);7.63 (2H, d, J=8.2 Hz); 8.04 (2H, d, J=8.5 Hz).

Example 81 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-ethoxyphenyl)-cyclohexanecarboxylate (PX118925)

The title compound was obtained from4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-ethoxyphenyl)cyclohexane-carboxylate (24a) by a method analogous tothat described for 4-[(hydroxyamino)carbonyl]phenyl 1-(4-methoxyphenyl)-cyclohexanecarboxylate (PX118478). After filtration of the catalyst andevaporation of methanol the crude product was crystallized from diethylether to give the title compound in 31% yield, m.p. 140-143° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.23-1.85 (8H, m); 1.32 (3H, t, J=6.8 Hz); 2.34-2.55(2H, m, overlapped with a signal of DMSO); 4.01 (2H, q, J=6.8 Hz); 6.95(2H, d, J=8.8 Hz); 7.00 (2H, d, J=8.6 Hz); 7.38 (2H, d, J=8.8 Hz); 7.76(2H, d, J=8.6 Hz); 9.05 (1H, s); 11.23 (1H, s). HPLC analysis onKromasil 100 C₁₈ column: impurities 4% (column size 4.6×150 mm; mobilephase acetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV230 nm; sample concentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal.Calcd for C₂₂H₂₅NO₅, %: C, 68.91; H, 6.57; N, 3.65. Found, %: C, 68.85;H, 6.57; N, 3.67.

Example 82 tert-Butyl4-[1-({4-[(hydroxyamino)carbonyl]phenoxy}-carbonyl)cyclohexyl]benzoate(PX118926)

The title compound was obtained from tert-butyl4-{1-[(4-{(benzyloxy)[(benzyloxy)imino]methyl}phenoxy)carbonyl]-cyclohexyl}benzoate (b) by a method analogousto that described for the previous example, using methanol-dioxane (2:1)as a solvent. After filtration of the catalyst and evaporation ofmethanol-dioxane mixture the crude product was crystallized fromdichloromethane-petroleum ether (1:1) to give the title compound in. 75%yield, m.p. 143-147° C. (dec.). ¹H NMR (CDCl₃, HMDSO) δ: 1.23-1.94 (8H,m); 1.59 (9H, s); 2.51-2.68 (2H, m); 6.98 (2H, d, J=8.0 Hz); 7.53 (2H,d, J=8.4 Hz); 7.69 (2H, d, J=8.0 Hz); 7.75 (1H, br s); 7.99 (2H, d,J=8.4 Hz); 8.73 (1H, br s). HPLC analysis on Alltima C₁₈ column:impurities 3.5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 70:30; detector UV 230 nm; sampleconcentration 0.5 mg/ml; flow rate 1.2 ml/min; column temperature 40°C.). Anal. Calcd for C₂₅H₂₉NO₆*0.2*20H₂O containing 2% of inorganicimpurities, %: C, 66.41; H, 6.55; N, 3.10. Found, %: C, 66.44; H, 6.58;N, 3.06.

Example 83 4-[(Hydroxyamino)carbonyl]phenyl1-[4-(acetyloxy)phenyl]-cyclohexanecarboxylate (PX118959)

The title compound was obtained from4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl1-[4-(acetyloxy)phenyl]-cyclohexanecarboxylate (24c) by a methodanalogous to that described for the previous example, usingmethanol-dioxane (2:1) as a solvent. After filtration of the catalystand evaporation of methanol-dioxane the crude product waschromatographed on silica gel with petroleum ether-ethyl acetate (1:1)and chloroform-methanol (98:2) as eluents and crystallized from diethylether to give the title compound in 50% yield, m.p. 69° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.22-1.91 (8H, m); 2.27 (3H, s); 2.33-2.62 (2H, m,overlapped with a signal of DMSO); 7.04 (2H, d, J=8.5 Hz); 7.17 (2H, d,J=8.6 Hz); 7.52 (2H, d, J=8.6 Hz); 7.78 (2H, d, J=8.5 Hz); 9.05 (1H, d,J=1.6 Hz); 11.24 (1H, s). HPLC analysis on Zorbax SB-C₁₈ column:impurities 7% [the compound contained ca. 5% of a deacetylated analogue(i.e. 4-[(hydroxyamino)carbonyl]phenyl1-[4-(hydroxy)phenyl]-cyclohexanecarboxylate) as a major impurity](column size 4.6×150 mm; mobile phase acetonitrile−0.1% H₃PO₄, gradient10 min from 1:1 to 100:0; detector UV 230 nm; sample concentration 0.5mg/ml; flow rate 1.5 ml/min). Anal. Calcd for C₂₂H₂₃NO₆*0.5H₂O, %: C,65.01; H, 5.95; N, 3.45. Found, %: C, 64.88; H, 5.88; N, 3.16.

Example 84 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-methylphenyl)-cyclohexanecarboxylate (PX118966)

The title compound was obtained from4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-methylphenyl)cyclohexane-carboxylate (24d) by a method analogous tothat described for the previous example, using methanol-dioxane (2:1) asa solvent. After filtration of the catalyst and evaporation ofmethanol-dioxane the crude product was chromatographed on silica gelwith chloroform-methanol (96:4) as eluent to give the title compound in28% yield, m.p. 59-60° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.22-1.91 (8H, m);2.27 (3H, s); 2.33-2.62 (2H, m, overlapped with a signal of DMSO); 7.04(2H, d, J=8.5 Hz); 7.17 (2H, d, J=8.6 Hz); 7.52 (2H, d, J=8.6 Hz); 7.78(2H, d, J=8.5 Hz); 9.05 (1H, d, J=1.6 Hz); 11.24 (1H, s). HPLC analysison Alltima C₁₈ column: impurities 1% (column size 4.6×150 mm; mobilephase acetonitrile−0.1M phosphate buffer (pH 2.5), 70:30; detector UV215 nm; sample concentration 1.0 mg/ml; flow rate 1.0 ml/min). Anal.Calcd for C₂₁H₂₃NO₄*0.5H₂O, %: C, 69.60; H, 6.67; N, 3.86. Found, %: C,69.91; H, 6.65; N, 3.62.

Example 85 4-[(Hydroxyamino)carbonyl]phenyl 1-[1,1′-biphenyl]-4-yl-cyclohexanecarboxylate (PX119058)

The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl 1-[1,1′-biphenyl]-4-ylcyclohexanecarboxylate (e) by amethod analogous to that described for the previous example, usingdioxane as a solvent. After filtration of the catalyst and evaporationof the solvent the crude product was chromatographed on silica gel withchloroform-methanol (96:4) as eluent to give the title compound in 76%yield, foam. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.18-1.98 (8H, m); 2.43-2.64(2H, m, overlapped with a signal of DMSO); 7.07 (2H, d, J=8.7 Hz); 7.37(1H, t, J=7.1 Hz); 7.48 (2H, t, J=7.3 Hz); 7.58 (2H, d, J=8.4 Hz); 7.69(2H, d, J=8.0 Hz); 7.73 (2H, d, J=8.4 Hz); 7.78 (2H, d, J=8.7 Hz); 9.06(1H, s); 11.24 (1H, s). HPLC analysis on Omnispher C₁₈ column:impurities 1.5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 60:40; detector UV 220 nm; sampleconcentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd forC₂₆H₂₅NO₄*0.4 MeOH*0.1 EtOAc), %: C, 73.64; H, 6.32; N, 3.20. Found, %:C, 73.54; H, 6.11; N, 3.19.

Example 86 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-chlorophenyl)-cyclohexanecarboxylate (PX119059)

The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl 1-(4-chlorophenyl)cyclohexane-carboxylate (24f) by amethod analogous to that described for the previous example, usingdioxane as a solvent. After filtration of the catalyst and evaporationof the solvent the crude product was crystallized from diethyl ether togive the title compound in 58% yield, m.p. 145-146° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 1.20-1.95 (8H, m); 2.37-2.58 (2H, m, overlapped with a signalof DMSO); 7.04 (2H, d, J=8.5 Hz); 7.48 (2H, d, J=9.0 Hz); 7.51 (2H, d,J=9.0 Hz); 7.78 (2H, d, J=8.5 Hz); 9.07 (1H, s); 11.25 (1H, s). HPLCanalysis on Alltima C₁₈ column: impurities 3% (column size 4.6×150 mm;mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 55:45;detector UV 254 nm; sample concentration 1.0 mg/ml; flow rate 1.5ml/min). Anal. Calcd for C₂₀H₂₀ClNO₄, %: C, 64.26; H, 5.39; N, 3.75.Found, %: C, 63.91; H, 5.36; N, 3.70.

Example 87 4-[(Hydroxyamino)carbonyl]phenyl 1-(3-fluorophenyl)-cyclohexanecarboxylate (PX119061)

The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl 1-(3-fluorophenyl)cyclohexane-carboxylate (24g) by amethod analogous to that described for the previous example, usingdioxane as a solvent. After filtration of the catalyst and evaporationof the solvent the crude product was washed with diethyl ether to givethe pure title compound in 61% yield, m.p. 150-151° C. ¹H NMR (DMSO-d₆,HMDSO)δ: 1.15-1.95 (8H, m); 2.39-2.57 (2H, m, overlapped with a signalof DMSO); 7.04 (2H, d, J=8.6 Hz); 7.17 (1H, ddt, J=0.9, 2.7 and 8.4 Hz);7.29 (1H, dt, J=8.0 and 2.2 Hz); 7.30-7.37 (1H, m); 7.48 (1H, dt, J=6.4and 8.3 Hz); 7.78 (2H, d, J=8.6 Hz); 9.05 (1H, s); 11.23 (1H, br s).HPLC analysis on Alltima C₁₈ column: impurities 1% (column size 4.6×150mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 50:50;detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.5ml/min). Anal. Calcd for C₂₀H₂₀FNO₄, %: C, 67.22; H, 5.64; N, 3.92.Found, %: C, 66.67; H, 5.65; N, 3.85

Example 88 4-[(Hydroxyamino)carbonyl]phenyl 1-(2-fluorophenyl)-cyclohexanecarboxylate (PX119062)

The title compound was obtained from 4-(benzyloxy)[(benzyloxy)imino]methyl}phenyl 1-(2-fluorophenyl)cyclohexane-carboxylate (4h) by a methodanalogous to that described for the previous example, using dioxane as asolvent. After filtration of the catalyst and evaporation of the solventthe crude product was chromatographed on silica gel withchloroform-methanol (96:4) as eluent and crystallized from diethyl etherto give the title compound in 93% yield, m.p. 125-126° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.26-1.55 (1H, m); 1.56-2.14 (7H, m); 2.26-2.48 (2H,m); 7.05 (2H, d, J=8.5 Hz); 7.17-7.47 (3H, m); 7.60 (1H, dt, J=2.1 and8.0 Hz); 7.79 (2H, d, J=8.5 Hz); 9.06 (1H, s); 11.24 (1H, s). HPLCanalysis on Omnispher 5 C₁₈ column: impurities 1% (column size 4.6×150mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2:5), 55:45;detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.5ml/min). Anal. Calcd for C₂₀H₂₀FNO₄, %: C, 67.22; H, 5.64; N, 3.92.Found, %: C, 67.15; H, 5.57; N, 3.84.

Example 89 4-[(Hydroxyamino)carbonyl]phenyl 1-(2-chloro-4-fluorophenyl)-cyclohexanecarboxylate (PX119064)

The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl 1-(2-chloro-4-fluorophenyl)cyclohexane-carboxylate (24i)by a method analogous to that described for the previous example, usingdioxane as a solvent. After filtration of the catalyst and evaporationof the solvent the crude product was crystallized from diethyl ether togive the title compound in 53% yield, m.p. 164-165° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 1.28-1.52 (1H, m); 1.52-2.11 (7H, m); 2.34-2.60 (2H, m,overlapped with a signal of DMSO); 7.09 (2H, d, J=8.6 Hz); 7.29 (1H,ddd, J=2.8, 8,1 and 8.9 Hz); 7.50 (1H, dd, J=2.8 and 8.6 Hz); 7.73 (1H,dd, J=6.1 and 8.9 Hz); 7.78 (2H, d, J=8.6 Hz); 9.05 (1H, s); 11.23 (1H,s). HPLC analysis on Alltima C18 column: impurities 2% (column size4.6×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5),50:50; detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.5ml/min). Anal. Calcd for C₂₀H₁₉ClFNO₄, %: C, 61.31; H, 4.89; N, 3.57.Found, %: C, 61.31; H, 4.99; N, 3.37.

Example 90 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-fluorophenyl)-cyclohexanecarboxylate (PX119065)

The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl 1-(4-fluorophenyl)cyclohexane-carboxylate (24j) by amethod analogous to that described for the previous example, usingdioxane as a solvent. After filtration of the catalyst and evaporationof the solvent the crude product was crystallized from diethyl ether togive the title compound in 86% yield, m.p. 150-151° C. ¹H NMR (DMSO-d₆,HMDSO) δ: 1.16-1.94 (8H, m); 2.39-2.61 (2H, m, overlapped with a signalof DMSO); 7.03 (2H, d, J=8.5 Hz); 7.24 (2H, t, J=8.9 Hz); 7.53 (2H, dd,J=5.4 and 8.9 Hz); 7.78 (2H, d, J=8.5 Hz); 9.06 (1H, s); 11.24 (1H, s).HPLC analysis on Alltima C18 column: impurities 1% (column size 4.6×150mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 50:50;detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.5ml/min). Anal. Calcd for C₂₀H₂₀FNO₄, %: C, 67.22; H, 5.64; N, 3.92.Found, %: C, 66.89; H, 5.66; N, 3.92.

Example 91 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-bromophenyl)-cyclohexanecarboxylate (PX119084)

The title compound was obtained from4-{(benzyloxy)[(benzyloxy)imino]methyl]phenyl1-(4-bromophenyl)cyclohexane-carboxylate (24k) by a method analogous tothat described for the previous example, using methanol-dioxane (2:1) asa solvent. After filtration of the catalyst and evaporation ofmethanol-dioxane the crude product was chromatographed on silica gelwith petroleum ether-ethyl acetate (3:2) as eluent to give the titlecompound in 46% yield, foam. According to analytical data (¹H NMR,elemental analysis) the product contained ca. 12-15% of the debrominatedanalogue, i.e., 4-[(hydroxyamino)carbonyl]-phenyl1-phenylcyclohexanecarboxylate (PX118479) as an impurity. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.16-1.94 (8H, m); 2.34-2.56 (2H, m, overlapped witha signal of DMSO); 7.04 (2H, d, J=8.6 Hz); 7.45 (2H, d, J=8.6 Hz); 7.61(2H, d, J=8.6 Hz); 7.77 (2H, d, J=8.6 Hz); 9.05 (1H, s); 11.24 (1H, s).HPLC analysis on Chromolith Performance RP-18 C column: impurities 13%(column size 3.9×150 mm; mobile phase acetonitrile−0.1% H₃PO₄, 60:40;detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 2 ml/min).Anal. Calcd for C₂₀H₂₀BrNO₄*0.12 C₂₀H₂₁NO₄, %: C, 58.61; H, 4.94; N,3.35. Found, %: C, 58.59; H, 4.87; N, 3.42.

Example 92 Isopropyl4-[1-({4-[(hydroxyamino)carbonyl]phenoxy}-carbonyl)cyclohexyl]benzoate

The title compound was obtained from isopropyl4-{1-[(4-(benzyloxy)[(benzyloxy)imino]methyl}phenoxy)carbonyl]-cyclohexyl}benzoate (24l) by a methodanalogous to that described for the previous example, usingmethanol-dioxane (2:1) as a solvent. After filtration of the catalystand evaporation of methanol-dioxane the crude product waschromatographed on silica gel with chloroform-methanol (96:4) as eluentto give the title compound in 44% yield, foam. ¹H NMR (DMSO-d₆, HMDSO)δ: 1.09-1.98 (8H, m); 1.32 (6H, d, J=6.2 Hz); 2.38-2.60 (2H, m,overlapped with a signal of DMSO); 5.14 (1H, septet, J=6.2 Hz); 7.06(2H, d, J=8.4 Hz); 7.65 (2H, d, J=8.4 Hz); 7.77 (2H, d, J=8.4 Hz); 8.00(2H, d, J=8.4 Hz); 9.07 (1H, s); 11.25 (1H, s). HPLC analysis onChromolith RP-18C column: impurities 6.6% (column size 4.6×100 mm;mobile phase acetonitrile—0.1% H₃PO₄, 70:30; detector UV 254 nm; sampleconcentration 1 mg/ml; flow rate 1 ml/min). Anal. Calcd forC₂₄H₂₇NO₆*0.4H₂O, %: C, 66.62; H, 6.48; N, 3.24. Found, %: C, 66.77; H,6.36; N, 3.03.

Example 93 1-(4-Methoxyphenyl)cyclopentanecarbonyl chloride (25)

The title compound was obtained from 1-(4-methoxyphenyl)cyclopentanecarboxylic acid (1/2) by a method analogous to thatdescribed for 1-(4-methoxyphenyl) cyclohexanecarbonyl chloride (21a), inca. 100% yield. The crude product was immediately utilized in the nextstep of the synthesis without further purification.

Example 94 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-methoxyphenyl) cyclopentanecarboxylate (26)

The title compound was obtained from benzylN-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) and1-(4-methoxyphenyl) cyclopentanecarbonyl chloride (25) by a methodanalogous to that described for 4-{[(benzyloxy)amino]carbonyl} phenyl1-(4-methoxyphenyl) cyclohexanecarboxylate (22a), in 65% yield (on 1/2)as a mixture of 2 isomers (94:6). Major (less polar) isomer of 26: ¹HNMR (CDCl₃, HMDSO) δ: 1.50-2.19 (6H, m); 2.51-2.92 (2H, m); 3.78 (3H,s); 4.99 (2H, s); 5.11 (2H, s); 6.86 (2H, d, J=8.8 Hz); 6.89 (2H, d,J=8.8 Hz); 7.17-7.47 (12H, m); 7.79 (2H, d, J=8.8 Hz).

Example 95 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-methoxyphenyl)-cyclopentanecarboxylate (PX119063)

The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl 1-(4-methoxyphenyl)-cyclopentanecarboxylate (26) by amethod analogous to that described for 4-[(Hydroxyamino)carbonyl]phenyl1-(4-methoxyphenyl) -cyclohexanecarboxylate (PX118478), using dioxane asa solvent. After filtration of the catalyst and evaporation of thesolvent the crude product was washed with diethyl ether to give thetitle compound in 78% yield as crystals, m.p. 143-144° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.61-1.86 (4H, m); 1.86-2.08 (2H, m); 2.54-2.74 (2H,m); 3.75 (3H, s); 6.95 (2H, d, J=8.7 Hz); 7.01 (2H, d, J=8.5 Hz); 7.38(2H, d, J=8.7 Hz); 7.75 (2H, d, J=8.5 Hz); 9.04 (1H, s); 11.22 (1H, s).HPLC analysis on Alltima C₁₈ column: impurities 2% (column size 4.6×150mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 50:50;detector UV 230 nm; sample concentration 1.0 mg/ml; flow rate 1.5ml/min). Anal. Calcd for C₂₀H₂₁NO₅*0.1 EtOAc, %: C, 67.28; H, 6.03; N,3.85. Found, %: C, 67.00; H, 5.96; N, 3.78.

Example 96 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-hydroxyphenyl) cyclohexanecarboxylate (27)

To a solution of 4-{(benzyloxy)[(benzyloxy)imino]methyl}-phenyl1-[4-(acetyloxy)phenyl]-cyclohexanecarboxylate (24c) (0.429 g, 0.74mmol) in tetrahydrofuran (5 ml) under argon atmosphere at ice bathtemperature 2.46 N potassium 2-methyl-2-butanolate solution intetrahydrofuran (0.32 ml, 0.79 mmol) slowly (ca. over 3 minutes) wasadded and the reaction mixture was stirred at this temperature for 1.5hours. The mixture was poured into a mixture of ice water (30 ml) andsaturated NaH₂PO₄ solution (5 ml), extracted with benzene (2×25 ml), theorganic extract was washed with brine (15 ml), and dried (Na₂SO₄). Thesolvent was evaporated and the residue was chromatographed on silica gel(25 g) with toluene-ethyl acetate (95:5) as eluent to give the titlecompound (0.354 g, 89%) as a mixture of 2 isomers. The prevailing isomerof 27: ¹H NMR (CDCl₃, HMDSO) δ: 1.12-1.97 (8H, m); 2.29-2.74 (2H, m);4.97 (2H, s); 5.08 (2H, s); 6.75 (2H, d, J=8.8 Hz); 6.88 (2H, d, J=8.8Hz); 7.21-7.49 (12H, m); 7.79 (2H, d, J=8.8 Hz).

Example 974-{1-[(4-(Benzyloxy)[(benzyloxy)imino]methyl}phenoxy)carbonyl]cyclohexyl}phenylbenzoate (28a)

To a solution of 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl1-(4-hydroxyphenyl)-cyclohexanecarboxylate (27) (0.189 g, 0.35 mmol) andbenzoyl chloride (0.049 ml, 0.42 mmol) in tetrahydrofuran (4 ml) underargon atmosphere at ice bath temperature 4-dimethylaminopyridine (0.052g, 0.42 mmol) was added. The resulting mixture was stirred at roomtemperature until the starting material 27 disappeared (ca. 2 hours) andthen supplemented with benzene (25 ml). The obtained mixture was washedsuccessively with water (25 ml), brine (15 ml), and dried (Na₂SO₄). Thesolvents were evaporated and the residue was chromatographed on silicagel with petroleum ether-toluene (1:2) as eluent to give the titlecompound as a mixture of 2 isomers (7:3). ¹H NMR (CDCl₃, HMDSO) δ:1.15-1.91 (8H, m); 2.41-2.72 (2H, m); 5.02 (2H. 0.7, s); 5.06 (2H. 0.3,s); 5.12 (2H. 0.7, s); 5.16 (2H. 0.3, s); 6.94 (2H. 0.7, d, J=8.8 Hz);7.27-7.42 (12H+2H. 0.3, m); 7.45-7.69 (5H, m); 7.84 (2H. 0.7, d, J=8.8Hz); 7.94 (2H. 0.3, d, J=8.8 Hz); 8.15-8.24 (2H, m).

Example 98 4-{(Benzyloxy)[(benzyloxy)imino]methyl}phenyl1-{4-[(2,2-dimethylpropanoyl)oxy]phenyl}-cyclohexanecarboxylate (28b)

The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl 1-(4-hydroxyphenyl)cyclohexanecarboxylate (27) andpivaloyl chloride by a method analogous to that described for theprevious example, in 67% yield as a mixture of 2 isomers (2:1). ¹H NMR(200 MHz, CDCl₃, HMDSO) δ: 1.22-1.86 (8H, m); 1.33 (9H. 0.33, s); 1.34(9H. 0.66, s); 2.49-2.68 (2H, m); 5.01 (2H. 0.66, s); 5.03 (2H. 0.33,s); 5.12 (2H. 0.66, s); 5.14 (2H. 0.33, s); 6.91 (2H. 0.33, d, J=8.8Hz); 7.06 (2H. 0.66, d, J=8.8 Hz); 7.22-7.41 (12H+2H. 0.33, m); 7.48(2H. 0.66, d, J=8.8 Hz); 7.82 (2H. 0.66, d, J=8.6 Hz); 7.87 (2H. 0.33,d, J=8.8 Hz).

Example 994-[1-({4-[(Hydroxyamino)carbonyl]phenoxy}carbonyl)cyclohexyl]-phenylbenzoate (PX119085)

The title compound was obtained from4-{1-[(4-{(benzyloxy)[(benzyloxy)imino] methyl}phenoxy)carbonyl]-cyclohexyl}phenyl benzoate (28a) by a method analogousto that described for 4-[(hydroxyamino)carbonyl]phenyl1-(4-methoxyphenyl)-cyclohexanecarboxylate (PX118478), usingmethanol-dioxane (2:1) as a solvent. After filtration of the catalystand evaporation of methanol-dioxane the crude product waschromatographed on silica gel with chloroform-methanol (9:1) as eluentto give the title compound in 19% yield, m.p. 114-115° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.18-1.97 (8H, m); 2.33-2.69 (2H, m, overlapped witha signal of DMSO); 7.08 (2H, d, J=8.5 Hz); 7.36 (2H, d, J=8.6 Hz);7.55-7.69 (4H, m); 7.72-7.85 (3H, m); 8.15 (2H, d, J=7.8 Hz); 9.16 (1H,br s); 11.31 (1H, br s). HPLC analysis on Omnispher 5 C₁₈ column:impurities 4% (column size 4.6×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 60:40; detector UV 215 nm; sampleconcentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd forC₂₇H₂₅NO₆*0.5H₂O, %: C, 69.22; H, 5.59; N, 2.99. Found, %: C, 69.28; H,5.46; N, 2.79.

Example 100 4-[(Hydroxyamino)carbonyl]phenyl1-{4-[(2,2-dimethylpropanoyl)oxy]-phenyl}-cyclohexane-carboxylate(PX119086)

The title compound was obtained from 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl1-{4-[(2,2-dimethylpropanoyl)oxy]phenyl}-cyclohexanecarboxylate (28b) bya method analogous to that described for the previous example, usingmethanol-dioxane (2:1) as a solvent. After filtration of the catalystand evaporation of methanol-dioxane the crude product waschromatographed on silica gel with chloroform-methanol (9:1) as eluentto give the title compound in 26% yield, m.p. 124-125° C. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.13-1.96 (8H, m); 1.30 (9H, s); 2.41-2.58 (2H, m,overlapped with a signal of DMSO); 7.04 (2H, d, J=8.7 Hz); 7.15 (2H, d,J=8.6 Hz); 7.53 (2H, d, J=8.7 Hz); 7.78 (2H, d, J=8.6 Hz); 9.06 (1H, d,J=1.5 Hz); 11.24 (1H, d, J=1.2 Hz). HPLC analysis on Omnispher 5 C₁₈column: impurities 4.5% (column size 4.6×150 mm; mobile phaseacetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV 215 nm;sample concentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd forC₂₅H₂₉NO₆, %: C, 68.32; H, 6.65; N, 3.19. Found, %: C, 67.86; H, 6.61;N, 3.18.

Example 1014-[1-({4-[(Hydroxyamino)carbonyl]phenoxy}carbonyl)cyclohexyl]-benzoicacid (PX119102)

A mixture of tert-butyl4-[1-({4-[(hydroxyamino)carbonyl]phenoxy}-carbonyl)cyclohexyl]-benzoate(PX118926) (0.12 g, 0.27 mmol), dichloromethane (4 ml), andtrifluoroacetic acid (1 ml) was stirred under argon atmosphere at roomtemperature until the starting material disappeared (ca. 2 hours). Themixture was supplemented with ethyl acetate (150 ml), the obtainedsolution was washed successively with water (2×100 ml), brine (50 ml),and dried (Na₂SO₄). The solvents were evaporated and the residue waschromatographed on silica gel with chloroform-isopropanol (9:1) aseluent to give the title compound in 48% yield as crystals, m.p.169-170° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.18-2.05 (8H, m); 2.34-2.69 (2H,m, overlapped with a signal of DMSO); 7.05 (2H, d, J=8.5 Hz); 7.62 (2H,d, J=8.4 Hz); 7.78 (2H, d, J=8.5 Hz); 7.99 (2H, d, J=8.4 Hz); 9.09 (1H,br s); 11.26 (1H, br s). HPLC analysis on Chromasil 100 C₁₈ column:impurities 5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 60:40; detector UV 254 nm; sampleconcentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd forC₂₁H₂₁NO₆*0.25H₂O, %: C, 65.02; H, 5.59; N, 3.61. Found, %: C, 64.88; H,5.49; N, 3.45.

Example 102 4-{[(Benzyloxy)amino]carbonyl}phenyl1-[4-(acetyloxy)phenyl]cyclohexanecarboxylate (22e)

The title compound was obtained from N-(benzyloxy)-4-hydroxybenzamide(14) and 1-(4-acetoxyphenyl)cyclohexane-carbonyl chloride (3c) by themethod of Example 7 in 55% yield (based on 1/7). ¹H NMR (CDCl₃, HMDSO)δ: 1.03-2.08 (8H, m); 2.28 (3H, s); 2.37-2.79 (2H, m); 5.00 (2H, s);6.94 (2H, d, J=8.4 Hz); 7.09 (2H, d, J=8.8 Hz); 7.38 (5H, s); 7.46 (2H,d, J=8.4 Hz); 7.60 (2H, d, J=8.4 Hz); 8.42 (1H, br s).

Example 103 4-{[(Benzyloxy)amino]carbonyl}phenyl1-(4-hydroxyphenyl)cyclohexanecarboxylate (29)

The title compound was obtained from4-{[(benzyloxy)amino]carbonyl}phenyl1-[4-(acetyloxy)phenyl]cyclohexane-carboxylate (22e) and potassium2-methyl-2-butanolate by the method of Example 9 in 65% yield. ¹H NMR(DMSO-d₆, HMDSO) δ: 1.14-1.93 (8H, m); 2.30-2.63 (2H, m, overlapped witha signal of DMSO); 4.90 (2H, s); 6.78 (2H, d, J=8.8 Hz); 7.02 (2H, d,J=8.8 Hz); 7.26 (2H, d, J=8.8 Hz); 7.27-7.55 (5H, m); 7.74 (2H, d, J=8.8Hz); 9.40 (1H, brs); 11.58 (1H, brs).

Example 104 4-[(Hydroxyamino)carbonyl]phenyl 1-(4-hydroxyphenyl)-cyclohexanecarboxylate (PX119103)

The title compound was obtained from4-{[(benzyloxy)amino]carbonyl}phenyl1-(4-hydroxyphenyl)cyclohexane-carboxylate (29) by the method of Example8 using methanol-dioxane (2:1) as a solvent. After filtration of thecatalyst and evaporation of methanol-dioxane the crude product wascrystallized from diethyl ether to give the title compound in 77% yield,m.p. 93-94° C. ¹H NMR (DMSO-d₆, HMDSO) δ: 1.18-2.05 (8H, m); 2.34-2.69(2H, m, overlapped with a signal of DMSO); 7.05 (2H, d, J=8.5 Hz); 7.62(2H, d, J=8.4 Hz); 7.78 (2H, d, J=8.5 Hz); 7.99 (2H, d, J=8.4 Hz); 9.09(1H, br s); 11.26 (1H, br s). HPLC analysis on Chromasil 100 C₁₈ column:impurities 5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1Mphosphate buffer (pH 2.5), 60:40; detector UV 254 nm; sampleconcentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd forC₂₀H₂₁NO₅*0.5H₂O*0.8 Et₂O, %: C, 65.77; H, 7.14; N, 3.31. Found, %: C,65.86; H, 7.11; N, 3.15.

Biological Activity

Candidate compounds were assessed for their ability to inhibitdeacetylase activity (biochemical assays) and to inhibit cellproliferation (cell-based antiproliferation assays), as described below.

Primary Assay (1): Deacetylase Activity

Briefly, this assay relies on the release of radioactive acetate from aradioactively labelled histone fragment by the action of HDAC enzyme.Test compounds, which inhibit HDAC, reduce the yield of radioactiveacetate. Signal (e.g., scintillation counts) measured in the presenceand absence of a test compound provide an indication of that compound'sability to inhibit HDAC activity. Decreased activity indicates increasedinhibition by the test compound.

The histone fragment was an N-terminal sequence from histone H4, and itwas labelled with radioactively labelled acetyl groups using tritiatedacetylcoenzyme A (coA) in conjunction with an enzyme which is thehistone acetyltransferase domain of the transcriptional coactivatorp300. 0.33 mg of peptide H4 (the N-terminal 20 amino acids of histoneH4, synthesized using conventional methods) were incubated withHis6-tagged p300 histone acetyltransferase domain (amino acids1195-1673, expressed in E. coli strain BLR(DE3)pLysS (Novagen, Cat. No.69451-3) and 3H-acetyl coA (10 μL of 3.95 Ci/mmol; from Amersham) in atotal volume of 300 μL of HAT buffer (50 mM Tris CI pH 8, 5% glycerol,50 mM KCl, 0.1 mM ethylenediaminetetraacetic acid (EDTA), 1 mmdithiothreitol (DTT) and 1 mM 4-(2-aminoethyl)-benzenesulfonylfluoride(AEBSF)). The mixture was incubated at 30° C. for 45 minutes after whichthe His-p300 was removed using nickel-trinitriloacetic acid agarose(Qiagen, Cat No. 30210). The acetylated peptide was then separated fromfree acetyl coA by size exclusion chromatography on Sephadex G-15 (SigmaG-15-120), using distilled H₂O as the mobile phase.

After purification of the radiolabelled histone fragment, it wasincubated with a source of HDAC (e.g., an extract of HeLa cells (a richsource of HDAC), recombinantly produced HDAC1 or HDAC2) and any releasedacetate was extracted into an organic phase and quantitativelydetermined using scintillation counting. By including a test compoundwith the source of HDAC, that compound's ability to inhibit the HDAC wasdetermined.

Primary Assay (2): Deacetylase Activity: Fluorescent Assay

Alternatively, the activity of the compounds as HDAC inhibitors wasdetermined using a commercially available fluorescent assay kit: (Fluorde Lys™, BioMol Research Labs, Inc., Plymouth Meeting, USA). HeLaextract was incubated for 1 hour at 37° C. in assay buffer (25 mM HEPES,137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂, pH 8.0) with 15 μM acetylatedsubstrate in the presence of test compound (HDAC inhibitor). The extentof deacetylation was determined by the addition of 50 μL of a 1-in-500dilution of Developer, and measurement of the fluorescence (excitation355 nm, emission 460 nm), according to the instructions provided withthe kit.

Extensive comparative studies have shown that Primary Assay (1) andPrimary Assay (2), discussed above, yield equivalent results. PrimaryAssay results reported herein are (a) exclusively from (1); (b)exclusively from (2); or (c) from both (1) and (2).

HeLa Cell Extract

The HeLa cell extract was made from HeLa cells (ATCC Ref. No. CCL-2) byfreeze-thawing three times in 60 mM Tris Cl pH 8.0, 450 mM NaCl, 30%glycerol. Two cell volumes of extraction buffer were used, andparticulate material was centrifuged out (20800 g, 4° C., 10 minutes).The supernatant extract having deacetylase activity was aliquotted andfrozen for storage.

Recombinantly Produced HDAC1 and HDAC2

Recombinant plasmids were prepared as follows.

Full length human HDAC1 was cloned by PCR using a λgt11 Jurkat cDNAlibrary (Clontech-HL5012b). The amplified fragment was inserted into theEcoRI-SalI sites of pFlag-CTC vector (Sigma-E5394), in frame with theFlag tag. A second PCR was carried out in order to amplify a fragmentcontaining the HDAC1 sequence fused to the Flag tag. The resultingfragment was subcloned into the EcoRI-SacI sites of the baculovirustransfer vector pAcHTL-C (Pharmingen-21466P).

Full length mouse HDAC2 was subcloned into pAcHLT-A baculovirus transfervector (Pharmingen-21464P) by PCR amplification of the EcoRI-SacIfragment from a HDAC2-pFlag-CTC construct.

Recombinant protein expression and purification was performed asfollows.

HDAC1 and HDAC2 recombinant baculoviruses were constructed usingBaculoGold Transfection Kit (Pharmingen-554740). Transfer vectors wereco-transfected into SF9 insect cells (Pharmingen-21300C). Amplificationof recombinant viruses was performed according to the PharmingenInstruction Manual. SF9 cells were maintained in serum-free SF900 medium(Gibco 10902-096).

For protein production, 2×10⁷ cells were infected with the appropriaterecombinant virus for 3 days. Cells were then harvested and spun at3,000 rpm for 5 minutes. They were then washed twice in PBS andresuspended in 2 pellet volumes of lysis buffer (25 mM HEPES pH 7.9, 0.1mM EDTA, 400 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Resuspendedcells were frozen on dry ice and thawed at 37° C. 3 times andcentrifuged for 10 minutes at 14,000 rpm. The supernatant was collectedand incubated with 300 μl of 50% Ni-NTA agarose bead slurry(Qiagen-30210). Incubation was carried out at 4° C. for 1 hour on arotating wheel. The slurry was then centrifuged at 500 g for 5 minutes.Beads were washed twice in 1 ml of wash buffer (25 mM HEPES pH7.9, 0.1mM EDTA, 150 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Protein waseluted 3 times in 300 μl elution buffer (25 mM HEPES pH 7.9, 0.1 mMEDTA, 250 mM KCl, 10% glycerol, 0.1% NP-40, 1 mM AEBSF) containingincreasing concentrations of imidazole: 0.2 M, 0.5 M and 1 M. Eachelution was performed for 5 minutes at room temperature. Eluted proteinwas kept in 50% glycerol at −70° C.

Assay Method

A source of HDAC (e.g., 2 μL of crude HeLa extract, 5 μL of HDAC1 orHDAC2; in elution buffer, as above) was incubated with 3 μL ofradioactively labelled peptide along with appropriate dilutions ofcandidate compounds (1.5 μL) in a total volume of 150 μL of buffer (20mM Tris pH 7.4, 10% glycerol). The reaction was carried out at 37° C.for one hour, after which the reaction was stopped by adding 20 μL of 1M HCl/0.4 M sodium acetate. Then, 750 μL of ethyl acetate was added, thesamples vortexed and, after centrifugation (14000 rpm, 5 minutes), 600μL from the upper phase were transferred to a vial containing 3 mL ofscintillation liquid (UltimaGold, Packard, Cat. No. 6013329).Radioactivity was measured using a Tri-Carb 2100TR Liquid ScintillationAnalyzer (Packard).

Percent activity (% activity) for each test compound was calculated as:% activity={(S ^(C) −B)/(S ^(o) −B)}×100wherein S^(C) denotes signal measured in the presence of enzyme and thecompound being tested, S^(o) denotes signal measured in the presence ofenzyme but in the absence of the compound being tested, and B denotesthe background signal measured in the absence of both enzyme andcompound being tested. The IC50 corresponds to the concentration whichachieves 50% activity.

IC50 data for several compounds of the present invention, as determinedusing this assay, are also shown in Table 1, below.

Measurement of cell viability in the presence of increasingconcentration of test compound at different time points is used toassess both cytotoxicity and the effect of the compound on cellproliferation.

Secondary Assay: Cell Proliferation

Compounds with HDAC inhibition activity, as determined using the primaryassay, were subsequently evaluated using secondary cell-based assays.The following cell lines were used:

-   HeLa—Human cervical adenocarcinoma cell line (ATCC ref. No. CCL-2).-   K11—HPV E7 transformed human keratinocyte line provided by Pidder    Jansen-Duerr, Institut für Biomedizinische Alternsforschung,    Innsbruck, Austria.-   NHEK-Ad—Primary human adult keratinocyte line (Cambrex Corp., East    Rutherford, N.J., USA).-   JURKAT—Human T-cell line (ATCC no. TIB-152).    Assay Method

Cells were cultured, exposed to candidate compounds, and incubated for atime, and the number of viable cells was then assessed using the CellProliferation Reagent WST-1 from Boehringer Mannheim (Cat. No. 1 644807), described below.

Cells were plated in 96-well plates at 3-10×10³ cells/well in 100 μL ofculture medium. The following day, different concentrations of candidatecompounds were added and the cells incubated at 37° C. for 48 hours.Subsequently, 10 μL/well of WST-1 reagent was added and the cellsreincubated for 1 hour. After the incubation time, absorbance wasmeasured.

WST-1 is a tetrazolium salt which is cleaved to formazan dye by cellularenzymes. An expansion in the number of viable cells results in anincrease in the overall activity of mitochondrial dehydrogenases in thesample. This augmentation in the enzyme activity leads to an increase inthe amount of formazan dye formed, which directly correlates to thenumber of metabolically active cells in the culture. The formazan dyeproduced is quantified by a scanning multiwell spectrophotometer bymeasuring the absorbance of the dye solution at 450 nm wavelength(reference wavelength 690 nm).

Percent activity (% activity) in reducing the number of viable cells wascalculated for each test compound as:% activity={(S ^(C) −B)/(S ^(o) −B)}×100wherein S^(C) denotes signal measured in the presence of the compoundbeing tested, S^(o) denotes signal measured in the absence of thecompound being tested, and B denotes the background signal measured inblank wells containing medium only. The IC50 corresponds to theconcentration which achieves 50% activity. IC50 values were calculatedusing the software package Prism 3.0 (GraphPad Software Inc., San Diego,Calif.), setting top value at 100 and bottom value at 0.

IC50 data for several compounds of the present invention, as determinedusing this assay, are also shown in Table 2, below.

Measurement of cell viability in the presence of increasingconcentration of test compound at different time points is used toassess both cytotoxicity and the effect of the compound on cellproliferation.

Biological Data

IC50 (or percent activity) data for several compounds of the presentinvention, as determined using the assays described above are summarisedin Table 1 and Table 2, below.

TABLE 1 Biochemical Assay Data HDAC Inhibition Compound (IC50 unlessotherwise specified) No. Ref. HeLa HDAC1 HDAC2 TSA  5 nM 15 nM 17 nMSAHA 189 nM — — 1 PX118478  23 nM — — 2 PX118479  52 nM — — 3 PX118480 25 nM — — 4 PX119063  85 nM — —

TABLE 2 Cell-Based Antiproliferation Assay Data Cell ProliferationInhibition WST-1 Compound (IC50 unless otherwise specified) No. Ref.HeLa K11 NHEK-AD Jurkat TSA 350 nM 0.38 μM  0.2 μM   42 nM Oxamflatin —4.82 μM 3.53 μM  170 nM MS-275 — 9.16 μM  3.1 μM  365 nM SAHA — 6.82 μM5.37 μM  750 nM 1 PX118478  4.6 μM 13.6 μM —  500 nM 2 PX118479 13.7 μM21.3 μM — 1.25 μM 3 PX118480  7.9 μM 1.65 μM —  780 nM 4 PX119063  4.9μM — — —

The foregoing has described the principles, preferred embodiments, andmodes of operation of the present invention. However, the inventionshould not be construed as limited to the particular embodimentsdiscussed. Instead, the above-described embodiments should be regardedas illustrative rather than restrictive, and it should be appreciatedthat variations may be made in those embodiments by workers skilled inthe art without departing from the scope of the present invention asdefined by the appended claims.

REFERENCES

A number of patents and publications are cited herein in order to morefully describe and disclose the invention and the state of the art towhich the invention pertains. Full citations for these references areprovided herein. Each of these references is incorporated herein byreference in its entirety into the present disclosure.

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1. A compound of the formula:

wherein: J is a linking functional group and is independently: —C(═O)-or —O—C(═O)— or —C(═O)—O—; Cy is a cyclyl group and is independently:C₃₋₂₀carbocyclyl, C₃₋₂₀heterocyclyl, or C₅₋₂₀aryl; and is optionallysubstituted; Q¹ is a cyclyl leader group, and is independently adivalent bidentate group obtained by removing two hydrogen atoms from aring carbon atom of a saturated monocyclic hydrocarbon having from 4 to7 ring atoms, or by removing two hydrogen atoms from a ring carbon atomof saturated monocyclic heterocyclic compound having from 4 to 7 ringatoms including 1 nitrogen ring atom or 1 oxygen ring atom; and isoptionally substituted; If J is—O—C(═O)— or C(═O)—O—, then: Q² is anacid leader group, and is independently: C₁₋₈ alkylene; and isoptionally substituted; or: Q² is an acid leader group, and isindependently: C₅₋₂₀arylene; C₅₋₂₀arylene-C₁₋₇alkylene;C₁₋₇alkylene-C₅₋₂₀arylene; or, C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene;and is optionally substituted; if J is—C(═O)—, then: Q² is an acidleader group, and is independently: C₅₋₂₀arylene;C₅₋₂₀arylene-C₁₋₇alkylene; C₁₋₇alkylene-C₅₋₂₀arylene; or,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene; and is optionally substituted;and pharmaceutically acceptable salts, solvates, amides, esters, ethers,chemically protected forms, and prodrugs thereof.
 2. A compoundaccording to claim 1, wherein J is —O—C(═O)— or —C(═O)—O—.
 3. A compoundaccording to claim 1, wherein J is —O—C(═O)—.
 4. A compound according toclaim 1, wherein J is —C(═O)—O—.
 5. A compound according to claim 1,wherein J is —C(═O)—.
 6. A compound according to claim 1, wherein Q¹ isindependently a group of the formula:

wherein: the ring independently has from 4 to 7 ring atoms; Z isindependently—CH₂—, —N(R^(N)) — or —O—; R^(N,) if present, isindependently —H, C₁₋₇alkyl, C₅₋₂₀aryl —C₁₋₇alkyl, C₀₃₂₀ heterocyclyl,or C₅₋₂₀aryl; and Q¹ is optionally further substituted.
 7. A compoundaccording to claim 6, wherein Q¹ is independently a group of theformula:

wherein y is independently 1, 2, 3, or
 4. 8. A compound according toclaim 7, wherein Q¹ is independently selected from:


9. A compound according to claim 8, wherein Q¹ is independently:


10. A compound according to claim 8, wherein Q¹ is independently:


11. A compound according to claim 8, wherein Q¹ is independently:


12. A compound according to claim 6, whereinR^(N if present, is independently selected from:—H, -Me, -Et, -Ph, and—CH)₂-Ph.
 13. A compound according to claim 6, whereinR^(N if present, is independently —H.)
 14. A compound according to claim1, wherein substituents on Q^(1,) if present, are independently selectedfrom: —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —O(iPr), —Ph, —C(═O)Me,—NH_(2,) —NMe_(2,) —NEt_(2,) morpholino, —CONH_(2,) -CONMe_(2,) —NHCOMe,and ═0; and wherein, if a substituent is on an arylene group, it mayadditionally be selected from: —Me, —Et, -iPr, -tBu, —CF_(3.)
 15. Acompound according to claim 1, wherein Cy is independentlyC₃₋₂₀carbocyclyl; and is optionally substituted.
 16. A compoundaccording to claim 1, wherein Cy is independently C₃₋₂₀heterocyclyl; andis optionally substituted.
 17. A compound according to claim 1, whereinCy is independently C₅₋₂₀aryl; and is optionally substituted.
 18. Acompound according to claim 1, wherein Cy is independentlyC₅₋₂₀carboaryl or C₅₋₂₀heteroaryl; and is optionally substituted.
 19. Acompound according to claim 1, wherein Cy is independently C₅₋₂₀arylderived from one of the following: benzene, pyridine, furan, indole,pyrrole, imidazole, naphthalene, quinoline, benzimidazole,benzothiofuran, fluorene, acridine, and carbazole; and is optionallysubstituted.
 20. A compound according to claim 1, wherein Cy isindependently C₅₋₂₀aryl derived from benzene and is optionallysubstituted.
 21. A compound according to claim 1, wherein Cy isindependently an optionally substituted phenyl group of the formula:

wherein n is independently an integer from 0 to 5, and each R^(A) isindependently a substituent.
 22. A compound according to claim 21,wherein n is
 0. 23. A compound according to claim 21, wherein n is 1,and the R^(A) group is in the 4′-position.
 24. A compound according toclaim 21, wherein n is 2, and one R^(A) group is in the 4 ′-position,and the other R^(A) group is in the 2′-position.
 25. A compoundaccording to claim 21, wherein n is 2, and one R^(A) group is in the 4′position, and the other RA group is in the 3′ position.
 26. A compoundaccording to claim 1, wherein each of the substituents on Cy, ifpresent, is independently selected from: (1) ester; (2) amido; (3) acyl;(4) halo; (5) hydroxy; (6) ether; (7) C17alkyl; substituted C17alkyl;(8) C52oaryl; substituted C52oaryl; (9) sulfonyl; (10) sulfonamido. 27.A compound according to claim 1, wherein each of the substituents on Cy,if present, is independently selected from: (1)—C(═O)OR^(1, wherein R) ¹is independently C₁₋₇alkyl as defined in (7); (2)—C(═O)NR²R^(3,) whereineach of R² and R³ is independently—H or C₁₋₇alkyl as defined in (7);(3)—C(═O)R^(4,) wherein R⁴ is independently C₁₋₇alkyl as defined in (7)or C₅₋₂₀aryl as defined in (8); (4)—F, —Cl, —Br, —I; (5)—OH; (6)—OR^(5,)wherein R⁵ is independently C₁₋₇alkyl as defined in (7) or C₅₋₂₀aryl asdefined in (8); (7) C₁₋₇alkyl; substituted C₁₋₇alkyl; halo-C₁₋₇alkyl;amino-C₁₋₇alkyl; carboxy-C₁₋₇alkyl; hydroxy-C₁₋₇alkyl;C₁₋₇alkoxy-C₁₋₇alkyl; C₅₋₂₀aryl-C₁₋₇alkyl; (8) C₅₋₂₀aryl; substitutedC₅₋₂₀aryl; (9)—SO₀₂R^(7,) wherein R⁷ is independently C₁₋₇alkyl asdefined in (7) or C₅₋₂₀aryl as defined in (8); (10)—SO₂NR⁸R^(9,) whereineach of R⁸ and R⁹ is independently—H or C₁₋₇alkyl as defined in (7). 28.A compound according to claim 1, wherein each of the substituents on Cy,if present, is independently selected from: (1)—C(═O)OMe, —C(═O)OEt,—C(═O)O(Pr), —C(═O)O(iPr), —C(═O)O(nBu), —C(═O)O(sBu), —C(═O)O(iBu),—C(═O)O(tBu), —C(═O)O(nPe); —C(═O)OCH₂CH₂OH, —C(═O)OCH₂CH₂OMe,—C(═O)OCH₂CH₂OEt; (2)—(C═O)NH_(2,) —(C═O)NMe_(2,) —(C═O)NEt_(2,)—(C═O)N(iPr)_(2,) —(C═0)N (CH₂CH₂OH)_(2;) (3) —(C═O)Me, —(C═O)Et,—(0═0)-cHex, —(C═O)Ph; (4) —F, —Cl, —Br, —I; (5) —OH; (6—OMe, —GEt,—O(iPr), —O(tBu), —OPh; —OCF_(3,) —OCH₂CF_(3;) —OCH₂CH₂OH, —OCH₂CH₂OMe,—OCH₂CH₂OEt; —OCH₂CH₂NH_(2,) —OCH₂CH₂NMe_(2,) —OCH₂CH₂N(iPr)_(2;) —OPh,—OPh-Me, —Oph-OH, —Oph-OMe, O-Ph-F, —Oph-CI, —Oph-Br, —Oph-I; (7) -Me,-Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe; —CF_(3,) —CH₂CF₃;—CH₂CH₂OH, —CH₂CH₂OMe, —CH₂CH₂OEt; —CH₂CH₂NH_(2,) —CH₂CH₂NMe_(2,)—CH₂CH₂N(iPr)_(2;) —CH₂-Ph; (8)-Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-F,-Ph-Cl, -Ph-Br, -Ph-I; (9)—SO₂Me, —SO₂Et, —SO₂Ph; (10)—SO₂NH_(2,)—SO₂NMe_(2,) —SO₂NEt_(2.)
 29. A compound according to claim 1, whereineach of the substituents on Cy, if present, is independently selectedfrom: —C(═O)OMe, —OMe, —C(═O)Me, —SO₂Me, —SO₂NMe_(2,) —C(═O)NH_(2,)—OCF_(3,) and—CH₂CH₂OH.
 30. A compound according to claim 1, wherein theacid leader group, Q^(2,) is independently: C₅₋₂₀arylene; and isoptionally substituted.
 31. A compound according to claim 1, wherein Q²is independently C₅₋₆arylene; and is optionally substituted.
 32. Acompound according to claim 1, wherein Q² is independently phenylene;and is optionally substituted.
 33. A compound according to claim 32,wherein the phenylene linkage is meta or para.
 34. A compound accordingto claim 32, wherein the phenylene linkage is meta.
 35. A compoundaccording to claim 32, wherein the phenylene linkage is para.
 36. Acompound according to claim 30, wherein Q² is independentlyunsubstituted.
 37. A compound according to claim 1, wherein J is—O—C(═O)— or —C(═O)—O— and the acid leader group, Q^(2,) isindependently: C₁₋₈alkylene; and is optionally substituted.
 38. Acompound according to claim 1, wherein J is —P—C(═O)— or —C(═O)—O— andQ² is independently: (a) a saturated C₁₋₇alkylene group; or: (b) apartially unsaturated C₂₋₇alkylene group; or: (c) an aliphaticC₁₋₇alkylene group; or: (d) a linear C₁₋₇alkylene group; or: (e) abranched C₂₋₇alkylene group; or: (f) a saturated aliphatic C₁₋₇alkylenegroup; or: (g) a saturated linear C₁₋₇alkylene group; or: (h) asaturated branched C₂₋₇alkylene group; or: (i) a partially unsaturatedaliphatic C₂₋₇alkylene group; or: (j) a partially unsaturated linearC₂₋₇alkylene group; or: (k) a partially unsaturated branchedC₂₋₇alkylene group; and is optionally substituted.
 39. A compoundaccording to claim 1, wherein J is—O—C(═O)— or —C(═O)—O— and Q² isindependently selected from: —(CH₂)₅—; —(CH₂)₆—; —(CH₂)₇—; and —(CH₂)₈—.40. A compound according to claim 1, wherein Q² is independently:C₅₋₂₀arylene-C₁₋₇alkylene; C₁₋₇alkylene-C₅₋₂₀arylene; or,C₁₋₇alkylene-C₅₋₂₀arylene-C₁₋₇alkylene; and is optionally substituted.41. A compound according to claim 1, wherein Q² is independently:C₅₋₆arylene-C₁₋₇alkylene; C₁₋₇alkylene-C₅₋₆arylene; or,C₁₋₇alkylene-C₅₋₆arylene-C₁₋₇alkylene; and is optionally substituted.42. A compound according to any claim 1, wherein Q² is independently:phenylene-C₁₋₇alkylene; C₁₋₇alkylene-phenylene; or,C₁₋₇alkylene-phenylene-C₁₋₇alkylene; and is optionally substituted. 43.A compound according to claim 1, wherein Q² independently has a backboneof from 5 to 6 atoms.
 44. A compound according to claim 1, wherein eachof the substituents on Q^(2,) if present, is independently selectedfrom: halo, hydroxy, ether, C₁₋₇alkoxy, C₅₋₂₀aryl, acyl, amino, amido,acylamido, nitro, and oxo; and wherein, if a substituent is on anarylene group, it may additionally be selected from: C₁₋₇alkyl andsubstituted C₁₋₇alkyl.
 45. A compound according to claim 1, wherein eachof the substituents on Q^(2,) if present, is independently selectedfrom: —F, —Cl, —Br, —I, —OH, —OMe, —OFt, —O(iPr), -Ph, —C(═O)Me,—NH_(2,) —NMe_(2,) —NEt_(2,) morpholino, —CONH_(2,) —CONMe_(2,) —NHCOMe,—NO_(2,) and ═O; and wherein, if a substituent is on an arylene group,it may additionally be selected from:-Me, -Et, -iPr, -tBu, —CF_(3.) 46.A compound of the formula:

wherein: J is independently:—C(═O)—O —; Q¹ is independently:

Q² is phenylene, and is optionally substituted; Cy is phenyl, and isoptionally substituted; and pharmaceutically acceptable salts, solvates,amides, esters, ethers, chemically protected forms, and prodrugsthereof.
 47. A compound selected from the following compounds, andpharmaceutically acceptable salts, solvates, amides, esters, ethers,chemically protected forms, and prodrugs thereof: 1

PX118478 2

PX118479 3

PX118480 4

PX119101 5

PX118925 6

PX118926 7

PX118959 8

PX118966 9

PX119058 10

PX119059 11

PX119061 12

PX119062 13

PX119064 14

PX119065 15

PX119084 16

PX119100 17

PX119063 18

PX119085 19

PX119086 20

PX119102 21

PX119103 22

23

24


48. A composition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 49. A method of inhibiting HDAC ina cell comprising contacting said cell with an effective amount of acompound according to claim
 1. 50. A method of inhibiting HDAC in asubject comprising administering to a subject an effective amount of acompound according to claim
 1. 51. A method of inhibiting HDAC in asubject comprising administering to a subject suffering from aproliferative condition an effective amount of a compound according toclaim 1, wherein the proliferative condition is selected from: cancer;psoriasis; a fibroproliferative disorder; liver fibrosis; smooth muscleproliferative disorder; atherosclerosis; restenosis; a neurodegenativedisease; Alzheimer's; Parkinson's; Huntington's chorea; amyotropiclateral sclerosis; spino-cerebellar degeneration; an inflammatorydisease; osteoarthritis; rheumatoid arthritis; a diseases involvingangiogenesis; rheumatoid arthritis; diabetic retinopathy; ahaematopoietic disorder; anaemia; sickle cell anaemia; thalassaeimia; afungal infection; a parasitic infection; malaria; trypanosomiasis;helminthiasis; a protozoal infection; a bacterial infection; a viralinfection; a condition treatable by immune modulation; multiplesclerosis; autoimmune diabetes; lupus; atopic dermatitis; an allergy;asthma; allergic rhinitis; and inflammatory bowel disease.
 52. A methodof inhibiting HDAC in a subject comprising administering to a subjectsuffering from cancer an effective amount of a compound according toclaim
 1. 53. A method of inhibiting HDAC in a subject comprisingadministering to a subject suffering from psoriasis an effective amountof a compound according to claim 1.